Substituted 8-arylquinolune PDE4 inhibitors

ABSTRACT

8-arylquinolines of formula (I) wherein the aryl group at the 8-position contains a meta two atom bridge to an optionally substituted phenyl or pyridyl group, are PDE4 inhibitors useful to treat asthma, chronic bronchitis, chronic obstructive pulmonary disease, arthritis, respiratory distress syndrome, allergic rhinitis, neurogenic inflammation, pain, rheumatoid arthritis, and other diseases. R 1 -R 7  and Ar are as in claim  1.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C.§371 of PCT Application No. PCT/CA02/00953, filed Jun. 26, 2002, whichclaims priority from U.S. Ser. No. 60/301,220, filed Jun. 27, 2001 and60/303,472, filed Jul. 6, 2001.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to compounds that are substituted8-arylquinolines. In particular, this invention is directed tosubstituted 8-arylquinolines which are phosphodiesterase-4 inhibitorswherein the aryl group at the 8-position contains a meta two carbon atombridge to an optionally substituted phenyl or pyridyl group.

2. Related Background

Hormones are compounds that variously affect cellular activity. In manyrespects, hormones act as messengers to trigger specific cellularresponses and activities. Many effects produced by hormones, however,are not caused by the singular effect of just the hormone. Instead, thehormone first binds to a receptor, thereby triggering the release of asecond compound that goes on to affect the cellular activity. In thisscenario, the hormone is known as the first messenger while the secondcompound is called the second messenger. Cyclic adenosine monophosphate(adenosine 3′,5′-cyclic monophosphate, “cAMP” or “cyclic AMP”) is knownas a second messenger for hormones including epinephrine, glucagon,calcitonin, corticotrophin, lipotropin, luteinizing hormone,norepinephrine, parathyroid hormone, thyroid-stimulating hormone, andvasopressin. Thus, cAMP mediates cellular responses to hormones. CyclicAMP also mediates cellular responses to various neurotransmitters.

Phosphodiesterases (“PDE”) are a family of enzymes that metabolize 3′,5′cyclic nucleotides to 5′ nucleoside monophosphates, thereby terminatingcAMP second messenger activity. A particular phosphodiesterase,phosphodiesterase-4 (“PDE4”, also known as “PDE-IV”), which is a highaffinity, cAMP specific, type IV PDE, has generated interest aspotential targets for the development of novel anti-asthmatic andanti-inflammatory compounds. PDE4 is known to exist as at lease fourisoenzymes, each of which is encoded by a distinct gene. Each of thefour known PDE4 gene products is believed to play varying roles inallergic and/or inflammatory responses. Thus, it is believed thatinhibition of PDE4, particularly the specific PDE4 isoforms that producedetrimental responses, can beneficially affect allergy and inflammationsymptoms. It would be desirable to provide novel compounds andcompositions that inhibit PDE4 activity.

Inhibition of PDE4 activity is believed effective for the treatment ofosteoporosis by reducing bone loss. For example, Ken-ici Miyamoto etal., Biochem. Pharmacology, 54:613-617(1997) describes the effect of aPDE4 on bone loss. Therefore, it would be desirable to provide novelcompounds and compositions that inhibit PDE4 activity.

A major concern with the use of PDE4 inhibitors is the side effect ofemesis which has been observed for several candidate compounds asdescribed in C. Burnouf et al. Ann. Rep. In Med. Chem., 33:91-109(1998).B. Hughes et al., Br. J. Pharmacol., 118:1183-1191(1996); M. J. Perry etal., Cell Biochem. Biophys., 29:113-132(1998); S. B. Christensen et al.,J. Med. Chem., 41:821-835(1998); and Burnouf (Ibid.) describe the widevariation of the severity of the undesirable side effects exhibited byvarious compounds. As described in M. D. Houslay et al., Adv. InPharmacol., 44:225-342(1998) and D. Spina et al., Adv. In Pharmacol.,44:33-89(1998), there is great interest and research of therapeutic PDE4inhibitors.

International Patent Publication WO9422852 describes quinolines as PDE4inhibitors.

A. H. Cook, et al., J. Chem. Soc., 413-417(1943) describesgamma-pyridylquinolines. Other quinoline compounds are described in KeiManabe et al., J. Org. Chem., 58(24):6692-6700(1993); Kei Manabe et al.,J. Am. Chem. Soc., 115(12):5324-5325(1993); and Kei Manabe et al., J.Am. Chem. Soc., 114(17):6940-6941(1992).

Compounds that include ringed systems are described by variousinvestigators as effective for a variety of therapies and utilities. Forexample, International Patent Publication No. WO 98/25883 describesketobenzamides as calpain inhibitors, European Patent Publication No. EP811610 and U.S. Pat. Nos. 5,679,712, 5,693,672 and 5,747,541 describesubstituted benzoylguanidine sodium channel blockers, U.S. Pat. No.5,736,297 describes ring systems useful as a photosensitive composition.

U.S. Pat. Nos. 5,491,147, 5,608,070, 5,622,977, 5,739,144, 5,776,958,5,780,477, 5,786,354, 5,798,373, 5,849,770, 5,859,034, 5,866,593,5,891,896, and International Patent Publication WO 95/35283 describePDE4 inhibitors that are tri-substituted aryl or heteroaryl phenylderivatives. U.S. Pat. No. 5,580,888 describes PDE4 inhibitors that arestyryl derivatives. U.S. Pat. No. 5,550,137 describes PDE4 inhibitorsthat are phenylaminocarbonyl derivatives. U.S. Pat. No. 5,340,827describes PDE4 inhibitors that are phenylcarboxamide compounds. U.S.Pat. No. 5,780,478 describes PDE4 inhibitors that are tetra-substitutedphenyl derivatives. International Patent Publication WO 96/00215describes substituted oxime derivatives useful as PDE4 inhibitors. U.S.Pat. No. 5,633,257 describes PDE4 inhibitors that are cyclo(alkyl andalkenyl)phenyl-alkenyl (aryl and heteroaryl) compounds.

However, there remains a need for novel compounds and compositions thattherapeutically inhibit PDE4 with minimal side effects.

SUMMARY OF THE INVENTION

The present invention is directed to novel substituted 8-arylquinolinesthat are PDE4 inhibitors, wherein the aryl group at the 8-positioncontains a meta two carbon atom bridge to an optionally substitutedphenyl or pyridyl group. This invention also provides a pharmaceuticalcomposition which includes an effective amount of the novel substituted8-arylquinoline and a pharmaceutically acceptable carrier.

This invention further provides a method of treatment in mammals of, forexample, asthma, chronic bronchitis, chronic obstructive pulmonarydisease (COPD), eosinophilic granuloma, psoriasis and other benign ormalignant proliferative skin diseases, endotoxic shock (and associatedconditions such as laminitis and colic in horses), septic shock,ulcerative colitis, Crohn's disease, reperfusion injury of themyocardium and brain, inflammatory arthritis, osteoporosis, chronicglomerulonephritis, atopic dermatitis, urticaria, adult respiratorydistress syndrome, infant respiratory distress syndrome, chronicobstructive pulmonary disease in animals, diabetes insipidus, allergicrhinitis, allergic conjunctivitis, vernal conjunctivitis, arterialrestenosis, atherosclerosis, neurogenic inflammation, pain, cough,rheumatoid arthritis, ankylosing spondylitis, transplant rejection andgraft versus host disease, hypersecretion of gastric acid, bacterial,fungal or viral induced sepsis or septic shock, inflammation andcytokine-mediated chronic tissue degeneration, osteoarthritis, cancer,cachexia, muscle wasting, depression, memory impairment, monopolardepression, acute and chronic neurodegenerative disorders withinflammatory components, Parkinson disease, Alzheimer's disease, spinalcord trauma, head injury, multiple sclerosis, tumour growth andcancerous invasion of normal tissues by the administration of aneffective amount of the novel substituted 8-arylquinoline or a precursorcompound which forms in vivo the novel substituted 8-arylquinoline.

DETAILED DESCRIPTION OF THE INVENTION

A compound of this invention is represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein

Ar is phenyl, pyridinone, pyridyl, or pyridyl N-oxide, optionallysubstituted with 1-5 independent —C₁₋₆alkyl, —OH, —CN, halogen, —CF₃,—(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl), —(C₀₋₆alkyl)-SO_(n)—NH—(C₁₋₆alkyl) or5-membered heteroaryl ring containing 1-4 heteroatoms independentlyselected from O, S or N, wherein the 5-membered-ring is optionallysubstituted with C₁₋₆alkyl, and the alkyl group- is optionallysubstituted with 1-3 independent —OH, —CN, halogen, or —CF₃;

R₁ is hydrogen, halogen; or a —C₁₋₆alkyl, -cycloC₃₋₆alkyl, —C₁₋₆alkenyl,—C₀₋₄alkyl-C(O)—C₀₋₄alkyl, —C₁₋₆alkoxy, aryl, heteroaryl, —CN,-heterocycloC₃₋₆alkyl, -amino, —C₁₋₆alkylamino,—C₁₋₆alkyl)(C₁₋₆alkyl)amino, —C₁₋₆alkyl(oxy)C₁₋₆alkyl, —C(O)NH(aryl),—C(O)NH(heteroaryl), —SO_(n)NH(aryl), —SO_(n)NH(heteroaryl),—SO_(n)NH(C₁₋₆alkyl), —C(O)N(C₀₋₆alkyl)(C₀₋₆alkyl),—NH—SO_(n)—(C₁₋₆alkyl), -carbamoyl, —(C₁₋₆alkyl)-O—C(CN)-dialkylamino,or —(C₁₋₆alkyl)-SO_(n)—C₁₋₆alkyl) group, wherein any of the groups isoptionally substituted with 1-5 substituents; wherein each substituentis independently a halogen, —OH, —CN, —C₁-C₆alkyl,—C(O)(heterocycloC₃₋₆alkyl), —C(O)—O—(C₀₋₆alkyl), —C(O)—O-aryl, alkoxy,cycloalkyloxy, acyl, acyloxy, -cycloC₃₋₆alkyl, heterocycloC₃₋₆alkyl,aryl, heteroaryl, pyridyl N-oxide, carbonyl, carbamoyl, or—SO_(n)—(C₁₋₆alkyl);

R₂, R₃, R₆, and R₇ are each independently hydrogen, halogen, hydroxyl,—C₁₋₆alkyl, or —C₁₋₆alkoxy, wherein the alkyl and alkoxy are optionallysubstituted with 1-3 independently halogen or OH;

R₄ is hydrogen, halogen, —CN, phenyl, oxadiazolyl, or —C(O)—O—C₀₋₆alkyl,wherein the phenyl, oxadiazolyl, or —C(O)—O—C₀₋₆alkyl is optionallysubstituted with 1-3 independent halogen, CN, CF3, —SO_(n)—C₁₋₆alkyl, orC₁₋₆alkyl substituents, and the alkyl group is optionally substitutedwith OH

R5 is hydrogen, hydroxyl, —CN; or a —C₁₋₆alkyl, —C(O)C₁₋₆alkyl,—C(O)-aryl, —C(O)-pyridyl, —C(O)—O—C₃₋₆alkyl, —C(O)—C₃₋₇cycloalkyl,—C₁₋₆alkyl-C₃₋₇cycloalkyl, —C₁₋₆alkyl(C₃₋₇cycloalkyl)₂, —C₁₋₆alkyl-aryl,—C(O)—N(C₀₋₆alkyl)₂, —SO_(n)aryl, —SO_(n)—C₁₋₆alkyl,—SO_(n)—C₃₋₇cycloalkyl, —SO_(n)—N(C₀₋₆alkyl)₂, —P(O)(C₁₋₆alkyl)₂,—P(O)(C₁₋₆alkoxy)₂, phenyl, pyridyl, —SO_(n)imidazolyl,—SO_(n)thiazolyl, 5-membered heteroaryl ring containing 1-4 heteroatomsindependently selected from O, S or N or oxoisoxaphosphinanyl group, anyof which group optionally substituted with 1-6 independent halogen,hydroxyl, —CN, —CF₃, —C₁₋₆alkyl, —SO_(n)—C₁₋₆alkyl, —C(O)—O—C₀₋₆alkyl,or hydroxyC₁₋₆alkyl substituents;

or R₅ and R₆ form ═O;

or R₆ and R₃ form —CH₂— or —O—; and

n is 0, 1, or 2.

In one aspect, the compound of this invention is represented by Formula(I) or a pharmaceutically acceptable salt thereof, wherein

Ar is phenyl, optionally substituted with 1-3 independent —C₁₋₆alkyl,—OH, —CN, halogen, —CF₃, —(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl),—(C₀₋₆alkyl)-SO_(n)—NH—(C₁₋₆alkyl) or 5-membered heteroaryl ringcontaining 1-4 heteroatoms independently selected from O, S or N,wherein the 5-membered-ring is optionally substituted with C₁₋₆alkyl,and the alkyl group- is optionally substituted with 1-3 independent —OH,—CN, halogen, or —CF₃;

R₁ is hydrogen, halogen; or a —C₁₋₆alkyl, -cycloC₃₋₆alkyl, —C₁₋₆alkenyl,—C₀₋₄alkyl-C(O)—C₀₋₄alkyl, —C₁₋₆alkoxy, aryl, heteroaryl, —CN,-heterocycloC₃₋₆alkyl, -amino, —C₁₋₆alkylamino,—C₁₋₆alkyl)(C₁₋₆alkyl)amino, —C₁₋₆alkyl(oxy)C₁₋₆alkyl, —C(O)NH(aryl),—C(O)NH(heteroaryl), —SO_(n)NH(aryl), —SO_(n)NH(heteroaryl),—SO_(n)NH(C₁₋₆alkyl), —C(O)N(C₀₋₆alkyl)(C₀₋₆alkyl),—NH—SO_(n)—(C₁₋₆alkyl), -carbamoyl, —(C₁₋₆alkyl)-O—C(CN)-dialkylamino,or —(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl) group, wherein any of the groups isoptionally substituted with 1-5 substituents; wherein each substituentis independently a halogen, —OH, —CN, —C₁-C₆alkyl,—C(O)(heterocycloC₃₋₆alkyl), —C(O)—O—(C₀₋₆alkyl), —C(O)—O-aryl, alkoxy,cycloalkyloxy, acyl, acyloxy, -cycloC₃₋₆alkyl, heterocycloC₃₋₆alkyl,aryl, heteroaryl, pyridyl N-oxide, carbonyl, carbamoyl, or—SO_(n)—C₁₋₆alkyl);

R₂, R₃, R₆, and R₇ are each independently hydrogen, halogen, hydroxyl,—C₁₋₆alkyl, or —C₁₋₆alkoxy, wherein the alkyl and alkoxy are optionallysubstituted with 1-3 independently halogen or hydroxyl;

R₄ is hydrogen, halogen, —CN, phenyl, oxadiazolyl, or —C(O)—O—C₀₋₆alkyl,wherein the phenyl, oxadiazolyl, or —C(O)—O—C₀₋₆alkyl is optionallysubstituted with 1-3 independent halogen, CN, CF3, —SO_(n)—C₁₋₆alkyl, orC₁₋₆alkyl substituents, and the alkyl group is optionally substitutedwith OH;

R5 is hydrogen, hydroxyl, —CN; or a —C₁₋₆alkyl, —C(O)C₁₋₆alkyl,—C(O)-aryl, —C(O)-pyridyl, —C(O)—O—C₀₋₆alkyl, —C(O)—C₃₋₇cycloalkyl,—C₁₋₆alkyl-C₃₋₇cycloalkyl, —C₁₋₆alkyl(C₃₋₇cycloalkyl)₂, —C₁₋₆alkyl-aryl,—C(O)—N(C₀₋₆alkyl)₂, —SO_(n)aryl, —SO_(n)—C₁₋₆alkyl,—SO_(n)—C₃₋₇cycloalkyl, —SO_(n)—N(C₀₋₆alkyl)₂, —P(O)(C₁₋₆alkyl)₂,—P(O)(C₁₋₆alkoxy)₂, phenyl, pyridyl, —SO_(n)imidazolyl,—SO_(n)thiazolyl, 5-membered heteroaryl ring containing 1-4 heteroatomsindependently selected from O, S or N or oxoisoxaphosphinanyl group, anyof which group optionally substituted with 1-6 independent halogen,hydroxyl, —CN, —CF₃, —C₁₋₆alkyl, —SO_(n)—C₁₋₆alkyl, —C(O)—O—C₀₋₆alkyl,or hydroxyC₁₋₆alkyl substituents;

or R₅ and R₆ form ═O;

or R₆ and R₃ form —CH₂— or —O—; and

n is 0, 1, or 2.

In an embodiment of this one aspect, the compound of this invention isrepresented by Formula (I) or a pharmaceutically acceptable saltthereof, wherein

Ar is phenyl, optionally substituted with 1-3 independent —C₁₋₆alkyl,—OH, —CN, halogen, —CF₃, —(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl),—(C₀₋₆alkyl)-SO_(n)—NH—(C₁₋₆alkyl) or 5-membered heteroaryl ringcontaining 1-4 heteroatoms independently selected from O, S or N,wherein the 5-membered-ring is optionally substituted with C₁₋₆alkyl,and the alkyl group- is optionally substituted with 1-3 independent —OH,—CN, halogen, or —CF₃;

R₁ is hydrogen, halogen; or a —C₁₋₆alkyl, -cycloC₃₋₆alkyl, —C₁₋₆alkenyl,—C₀₋₄alkyl-C(O)—C₀₋₄alkyl, —C₁₋₆alkoxy, aryl, heteroaryl, —CN,-heterocycloC₃₋₆alkyl, -amino, —C₁₋₆alkylamino,—(C₁₋₆alkyl)(C₁₋₆alkyl)amino, —C₁₋₆alkyl(oxy)C₁₋₆alkyl, —C(O)NH(aryl),—C(O)NH(heteroaryl), —SO_(n)NH(aryl), —SO_(n)NH(heteroaryl),—SO_(n)NH(C₁₋₆alkyl), —C(O)N(C₀₋₆alkyl)(C₀₋₆alkyl),—NH—SO_(n)—(C₁₋₆alkyl), -carbamoyl, —(C₁₋₆alkyl)-O—C(CN)-dialkylamino,or —(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl) group, wherein any of the groups isoptionally substituted with 1-5 substituents; wherein each substituentis independently a halogen, —OH, —CN, —C₁-C₆alkyl,—C(O)(heterocycloC₃₋₆alkyl), —C(O)—O—(C₀₋₆alkyl), —C(O)—O-aryl, alkoxy,cycloalkyloxy, acyl, acyloxy, -cycloC₃₋₆alkyl, heterocycloC₃₋₆alkyl,aryl, heteroaryl, pyridyl N-oxide, carbonyl, carbamoyl, or—SO_(n)—(C₁₋₆alkyl);

R₂, R₃, R₆, and R₇ are each independently hydrogen, halogen, hydroxyl,—C₁₋₆alkyl, or —C₁₋₆alkoxy, wherein the alkyl and alkoxy are optionallysubstituted with 1-3 independently halogen or hydroxyl;

R₄ is hydrogen, halogen, —CN, or —C(O)—O—C₀₋₆alkyl, wherein the—C(O)—O—C₀₋₆alkyl is optionally substituted with 1-3 independenthalogen, CN, CF3, —SO_(n)—C₁₋₆alkyl, or C₁₋₆alkyl substituents, and thealkyl group is optionally substituted with OH;

R5 is hydrogen, hydroxyl, —CN; or a —C₁₋₆alkyl, —C(O)C₁₋₆alkyl,—C(O)-aryl, —C(O)-pyridyl, —C(O)—O—C₀₋₆alkyl, —C(O)—C₃₋₇cycloalkyl,—C₁₋₆alkyl-C₃₋₇cycloalkyl, —C₁₋₆alkyl(C₃₋₇cycloalkyl)₂, —C₁₋₆alkyl-aryl,C(O)—N(C₀₋₆alkyl)₂, —SO_(n)aryl, —SO_(n)—C₁₋₆alkyl,—SO_(n)—C₃₋₇cycloalkyl, —SO_(n)—N(C₀₋₆alkyl)₂, —P(O)(C₁₋₆alkyl)₂,—P(O)(C₁₋₆alkoxy)₂, phenyl, pyridyl, —SO_(n)imidazolyl,—SO_(n)thiazolyl, 5-membered heteroaryl ring containing 1-4 heteroatomsindependently selected from O, S or Nor oxoisoxaphosphinanyl group, anyof which group optionally substituted with 1-6 independent halogen,hydroxyl, —CN, —CF₃, —C₁₋₆alkyl, —SO_(n)—C₁₋₆alkyl, —C(O)—O—C₀₋₆alkyl,or hydroxyC₁₋₆alkyl substituents;

or R₅ and R₆ form ═O;

or R₆ and R₃ form —CH₂— or —O—; and

n is 0, 1, or 2.

In another embodiment of this one aspect, the compound of this inventionis represented by Formula (I) or a pharmaceutically acceptable saltthereof, wherein

Ar is phenyl, optionally substituted with 1-3 independent —C₁₋₆alkyl,—OH, —CN, halogen, —CF₃, —(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl),—(C₀₋₆alkyl)-SO_(n)—NH—(C₁₋₆alkyl) or 5-membered heteroaryl ringcontaining 1-4 heteroatoms independently selected from O, S or N,wherein the 5-membered-ring is optionally substituted with C₁₋₆alkyl,and the alkyl group- is optionally substituted with 1-3 independent —OH,—CN, halogen, or —CF₃;

R₁ is hydrogen, halogen; or a —C₁₋₆alkyl, -cycloC₃₋₆alkyl, —C₁₋₆alkenyl,—C₀₋₄alkyl-C(O)—C₀₋₄alkyl, —C₁₋₆alkoxy, aryl, heteroaryl, —CN,-heterocycloC₃₋₆alkyl, -amino, —C₁₋₆alkylamino,—C₁₋₆alkyl)(C₁₋₆alkyl)amino, —C₁₋₆alkyl(oxy)C₁₋₆alkyl, —C(O)NH(aryl),—C(O)NH(heteroaryl), —SO_(n)NH(aryl), —SO_(n)NH(heteroaryl),—SO_(n)NH(C₁₋₆alkyl), —C(O)N(C₀₋₆alkyl)(C₀₋₆alkyl),—NH—SO_(n)—(C₁₋₆alkyl), -carbamoyl, —(C₁₋₆alkyl)-O—C(CN)-dialkylamino,or —(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl) group, wherein any of the groups isoptionally substituted with 1-5 substituents; wherein each substituentis independently a halogen, —OH, —CN, —C₁-C₆alkyl,—C(O)(heterocycloC₃₋₆alkyl), —C(O)—O—(C₀₋₆alkyl), —C(O)—O-aryl, alkoxy,cycloalkyloxy, acyl, acyloxy, -cycloC₃₋₆alkyl, heterocycloC₃₋₆alkyl,aryl, heteroaryl, pyridyl N-oxide, carbonyl, carbamoyl, or—SO_(n)—C₁₋₆alkyl);

R₂, R₃, R₆, and R₇ are each independently hydrogen, halogen, hydroxyl,—C₁₋₆alkyl, or —C₁₋₆alkoxy, wherein the alkyl and alkoxy are optionallysubstituted with 1-3 independently halogen or hydroxyl;

R₄ is oxadiazolyl optionally substituted with 1-3 independent halogen,CN, CF3, —SO_(n)—C₁₋₆alkyl, or C₁₋₆alkyl substituents, and the alkylgroup is optionally substituted with OH;

R5 is hydrogen, hydroxyl, —CN; or a —C₁₋₆alkyl, —C(O)C₁₋₆alkyl,—C(O)-aryl, —C(O)-pyridyl, —C(O)—O—C₀₋₆alkyl, —(O)C₃₋₇cycloalkyl,—C₁₋₆alkyl-C₃₋₇cycloalkyl, C₁₋₆alkyl(C₃₋₇cycloalkyl)₂, —C₁₋₆alkyl-aryl,—C(O)—N(C₀₋₆alkyl)₂, —SO_(n)aryl, —SO_(n)—C₁₋₆alkyl,—SO_(n)—C₃₋₇cycloalkyl, —SO_(n)—N(C₀₋₆alkyl)₂, —P(O)(C₁₋₆alkyl)₂,—P(O)(C₁₋₆alkoxy)₂, phenyl, pyridyl, —SO_(n)imidazolyl,—SO_(n)thiazolyl, 5-membered heteroaryl ring containing 1-4 heteroatomsindependently selected from O, S or N or oxoisoxaphosphinanyl group, anyof which group optionally substituted with 1-6 independent halogen,hydroxyl, —CN, —CF₃, —C₁₋₆alkyl, —SO_(n)—C₁₋₆alkyl, —C(O)—O—C₀₋₆alkyl,or hydroxy C₁₋₆alkyl substituents;

or R₅ and R₆ form ═O;

or R₆ and R₃ form —CH₂— or —O—; and

n is 0, 1, or 2.

In still another embodiment of this one aspect, the compound of thisinvention is represented by Formula (I) or a pharmaceutically acceptablesalt thereof, wherein

Ar is phenyl, optionally substituted with 1-3 independent —C₁₋₆alkyl,—OH, —CN, halogen, —CF₃, —(C₁₋₆alkyl)-SO_(n)—(C₁₋₆alkyl),—(C₀₋₆alkyl)-SO_(n)—NH—(C₁₋₆alkyl) or 5-membered heteroaryl ringcontaining 1-4 heteroatoms independently selected from O, S or N,wherein the 5-membered-ring is optionally substituted with C₁₋₆alkyl,and the alkyl group- is optionally substituted with 1-3 independent —OH,—CN, halogen, or —CF₃;

R₁ is hydrogen, halogen; or a —C₁₋₆alkyl, -cycloC₃₋₆alkyl, —C₁₋₆alkenyl,—C₀₋₄alkyl-C(O)—C₀₋₄alkyl, —C₁₋₆alkoxy, aryl, heteroaryl, —CN,-heterocycloC₃₋₆alkyl, -amino, —C₁₋₆alkylamino,—(C₁₋₆alkyl)(C₁₋₆alkyl)amino, —C₁₋₆alkyl(oxy)C₁₋₆alkyl, —C(O)NH(aryl),—C(O)NH(heteroaryl), —SO_(n)NH(aryl), —SO_(n)NH(heteroaryl),—SO_(n)NH(C₁₋₆alkyl), —C(O)N(C₀₋₆alkyl)(C₀₋₆alkyl),—NH—SO_(n)—(C₁₋₆alkyl), -carbamoyl, —(C₁₋₆alkyl)-O—C(CN)-dialkylamino,or —(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl) group, wherein any of the groups isoptionally substituted with 1-5 substituents; wherein each substituentis independently a halogen, —OH, —CN, —C₁-C₆alkyl,—C(O)(heterocycloC₃₋₆alkyl), —C(O)—O—(C₀₋₆alkyl), —C(O)—O-aryl, alkoxy,cycloalkyloxy, acyl, acyloxy, -cycloC₃₋₆alkyl, heterocycloC₃₋₆alkyl,aryl, heteroaryl, pyridyl N-oxide, carbonyl, carbamoyl, or—SO_(n)(C₁₋₆alkyl);

R₂ and R₇ are each independently hydrogen, halogen, hydroxyl,—C₁₋₆alkyl, or —C₁₋₆alkoxy, wherein the alkyl and alkoxy are optionallysubstituted with 1-3 independently halogen or hydroxyl;

R₄ is hydrogen, halogen, —CN, phenyl, oxadiazolyl, or —C(O)—O—C₀₋₆alkyl,wherein the phenyl, oxadiazolyl, or —C(O)—C₀₋₆alkyl is optionallysubstituted with 1-3 independent halogen, CN, CF3, —SO_(n)—C₁₋₆alkyl, orC₁₋₆alkyl substituents, and the alkyl group is optionally substitutedwith OH;

R5 is hydrogen, hydroxyl, —CN; or a —C₆alkyl, —C(O)C₁₋₆alkyl,—C(O)-aryl, —C(O)-pyridyl, —C(O)—O—C₀₋₆alkyl, —C(O)—C₃₋₇cycloalkyl,—C₁₋₆alkyl-C₃₋₇cycloalkyl, —C₁₋₆alkyl(C₃₋₇cycloalkyl)₂, —C₁₋₆alkyl-aryl,—C(O)—N(C₀₋₆alkyl)₂, —SO_(n)aryl, —SO_(n)—C₁₋₆alkyl,SO_(n)—C₃₋₇cycloalkyl, —SO_(n)—N(C₀₋₆alkyl)₂, —P(O)(C₁₋₆alkyl)₂,—P(O)(C₁₋₆alkoxy)₂, phenyl, pyridyl, —SO_(n)imidazolyl,—SO_(n)thiazolyl, 5-membered heteroaryl ring containing 1-4 heteroatomsindependently selected from O, S or N or oxoisoxaphosphinanyl group, anyof which group optionally substituted with 1-6 independent halogen,hydroxyl, —CN, —CF₃, —C₁₋₆alkyl, —SO_(n)—C₁₋₆alkyl, —C(O)—O—C₀₋₆alkyl,or hydroxyC₁₋₆alkyl substituents;

R₆ and R₃ form —CH₂—; and

n is 0, 1, or 2.

In still another embodiment of this one aspect, the compound of thisinvention is represented by Formula (I) or a pharmaceutically acceptablesalt thereof, wherein Ar is phenyl, optionally substituted with 1-3independent —C₁₋₆alkyl, —OH, —CN, halogen, —CF₃,—(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl), —(C₀₋₆alkyl)-SO_(n)—NH—(C₁₋₆alkyl) or5-membered heteroaryl ring containing 1-4 heteroatoms independentlyselected from O, S or N, wherein the 5-membered-ring is optionallysubstituted with C₁₋₆alkyl, and the alkyl group- is optionallysubstituted with 1-3 independent —OH, —CN, halogen, or —CF₃;

R₁ is —C₁₋₆alkyl, optionally substituted with 1-5 substituents; whereineach substituent is independently a halogen, —H, —CN, —C₁-C₆alkyl,—C(O)(heterocycloC₃₋₆alkyl), —C(O)O—(C₀₋₆alkyl), —(O)—O-aryl, alkoxy,cycloalkyloxy, acyl, acyloxy, -cycloC₃₋₆alkyl, heterocycloC₃₋₆alkyl,aryl, heteroaryl, pyridyl N-oxide, carbonyl, carbamoyl, or—SO_(n)—(C₁₋₆alkyl);

R₂, R₃, R₆, and R₇ are each independently hydrogen, halogen, hydroxyl,—C₁₋₆alkyl, or —C₁₋₆alkoxy, wherein the alkyl and alkoxy are optionallysubstituted with 1-3 independently halogen or hydroxyl;

R₄ is hydrogen, halogen, CN, phenyl, oxadiazolyl, or —C(O)—O—C₀₋₆alkyl,wherein the phenyl, oxadiazolyl, or —C(O)—O—C₀₋₆alkyl is optionallysubstituted with 1-3 independent halogen, CN, CF3, —SO_(n)—C₁₋₆alkyl, orC₁₋₆alkyl substituents, and the alkyl group is optionally substitutedwith OH

R5 is hydrogen, hydroxyl, —CN; or a —C₁₋₆alkyl, —C(O)C₁₋₆alkyl,—C(O)-aryl, —C(O)-pyridyl, —C(O)—O—C₀₋₆alkyl, —C(O)—C₃₋₇cycloalkyl,—C₁₋₆alkyl-C₃₋₇cycloalkyl, —C₁₋₆alkyl(C₃₋₇cycloalkyl)₂, —C₁₋₆alkyl-aryl,—C(O)—N(C₀₋₆alkyl)₂, —SO_(n)aryl, —SO_(n)—C₁₋₆alkyl,—SO_(n)—C₃₋₇cycloalkyl, —SO_(n)—N(C₀₋₆alkyl)₂, —P(O)(C₁₋₆alkyl)₂,—P(O)(C₁₋₆alkoxy)₂, phenyl, pyridyl, —SO_(n)imidazolyl,—SO_(n)thiazolyl, 5-membered heteroaryl ring containing 1-4 heteroatomsindependently selected from O, S or N group or oxoisoxaphosphinanylgroup, any of which group optionally substituted with 1-6 independenthalogen, hydroxyl, —CN, —CF3, —C₁₋₆alkyl, —SO_(n)—C₁₋₆alkyl,—C(O)—O—C₀₋₆alkyl, or hydroxyC₁₋₆alkyl substituents;

or R₅ and R₆ form ═O;

or R₆ and R₃ form —CH₂— or —O—; and

n is 0, 1, or 2.

In still another embodiment of this one aspect, the compound of thisinvention is represented by Formula (I) or a pharmaceutically acceptablesalt thereof, wherein

Ar is phenyl, optionally substituted with 1-3 independent —C₁₋₆alkyl,—OH, —CN, halogen, —CF₃, —(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl),—(C₀₋₆alkyl)-SO_(n)—NH—(C₁₋₆alkyl) or 5-membered heteroaryl ringcontaining 1-4 heteroatoms independently selected from O, S or N,wherein the 5-membered-ring is optionally substituted with C₁₋₆alkyl,and the alkyl group- is optionally substituted with 1-3 independent —OH,—CN, halogen, or —CF₃;

R₁ is —C₁₋₆alkyl, optionally substituted with 1-5 substituents; whereineach substituent is independently a halogen, —OH, —CN, —C₁-C₆alkyl,—C(O)(heterocycloC₃₋₆alkyl), —C(O)—O—(C₀₋₆alkyl), —C(O)—O-aryl, alkoxy,cycloalkyloxy, acyl, acyloxy, -cycloC₃₋₆alkyl, heterocycloC₃₋₆alkyl,aryl, heteroaryl, pyridyl N-oxide, carbonyl, carbamoyl, or—SO_(n)—(C₁₋₆alkyl);

R₂, and R₃ are each hydrogen;

R₄ is hydrogen;

R5 is hydrogen, hydroxyl, —CN; or a —C₁₋₆alkyl, —C(O)C₁₋₆alkyl,—C(O)-aryl, —C(O)-pyridyl, —C(O)—O—C₀₋₆alkyl, —C(O)—C₃₋₇cycloalkyl,—C₁₋₆alkyl-C₃₋₇cycloalkyl, —C₁₋₆alkyl(C₃₋₇cycloalkyl)₂, —C₁₋₆alkyl-aryl,—C(O)—N(C₀₋₆alkyl)₂, —SO_(n)aryl, —SO_(n)—C₁₋₆alkyl,—SO_(n)—C₃₋₇cycloalkyl, —SO_(n)—N(C₀₋₆alkyl)₂, —P(O)(C₁₋₆alkyl)₂,—P(O)(C₁₋₆alkoxy)₂, phenyl, pyridyl, —SO_(n)imidazolyl,—SO_(n)thiazolyl, 5-membered heteroaryl ring containing 1-4 heteroatomsindependently selected from O, S or N group or oxoisoxaphosphinanylgroup, any of which group optionally substituted with 1-6 independenthalogen, hydroxyl, —CN, —CF₃, —C₁₋₆alkyl, —SO_(n)—C₁₋₆alkyl,C(O)—O—C₀₋₆alkyl, or hydroxyC₁₋₆alkyl substituents;

R₆, and R₇ are each independently hydrogen, halogen, hydroxyl,—C₁₋₆alkyl, or —C₁₋₆alkoxy, wherein the alkyl and alkoxy are optionallysubstituted with 1-3 independently halogen or hydroxyl;

or R₅ and R₆ form ═O;

or R₆ and R₃ form —CH₂— or —O—; and

n is 0, 1, or 2.

In still another embodiment of this one aspect, the compound of thisinvention is represented by Formula (I) or a pharmaceutically acceptablesalt thereof, wherein

Ar is phenyl substituted with —(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl), and thealkyl group is optionally substituted with 1-3 independent —OH, —CN,halogen, or —CF₃;

R₁ is —C₁₋₆alkyl, optionally substituted with 1-5 substituents; whereineach substituent is independently a halogen, —OH, —CN, —C₁-C₆alkyl,—C(O)(heterocycloC₃₋₆alkyl), —C(O)—O—(C₀₋₆alkyl), —C(O)—O-aryl, alkoxy,cycloalkyloxy, acyl, acyloxy, -cycloC₃₋₆alkyl, heterocycloC₃₋₆alkyl,aryl, heteroaryl, pyridyl N-oxide, carbonyl, carbamoyl, or—SO_(n)—(C₁₋₆alkyl);

R₂, R₃, R₆, and R₇ are each independently hydrogen, halogen, hydroxyl,—C₁₋₆alkyl, or —C₁₋₆alkoxy, wherein the alkyl and alkoxy are optionallysubstituted with 1-3 independently halogen or hydroxyl;

R₄ is hydrogen, halogen, —CN, phenyl, oxadiazolyl, or —C(O)—O—C₀₋₆alkyl,wherein the phenyl, oxadiazolyl, or —C(O)—O—C₀₋₆alkyl is optionallysubstituted with 1-3 independent halogen, CN, CF3, —SO_(n-1)C₁₋₆alkyl,or C₁₋₆alkyl substituents, and the alkyl group is optionally substitutedwith OH

R5 is hydrogen, hydroxyl, —CN; or a —C₁₋₆alkyl, —C(O)C₁₋₆alkyl,—C(O)-aryl, —C(O)-pyridyl, —C(O)—O—C₀₋₆alkyl, —C(O)—C₃₋₇cycloalkyl,—C₁₋₆alkyl-C₃₋₇cycloalkyl, —C₁₋₆alkyl(C₃₋₇cycloalkyl)₂, —C₁₋₆alkyl-aryl,—C(O)—N(C₀₋₆alkyl)₂, —SO_(n)aryl, —SO_(n)—C₁₋₆alkyl,—SO_(n)—C₃₋₇cycloalkyl, —SO_(n)—N(C₀₋₆alkyl)₂, —P(O)(C₁₋₆alkyl)₂,—P(O)(C₁₋₆alkoxy)₂, phenyl, pyridyl, —SO_(n)imidazolyl,—SO_(n)thiazolyl, 5-membered heteroaryl ring containing 1-4 heteroatomsindependently selected from O, S or N group or oxoisoxaphosphinanylgroup, any of which group optionally substituted with 1-6 independenthalogen, hydroxyl, —CN, —CF₃, —C₁₋₆alkyl, —SO_(n)—C₁₋₆alkyl,—C(O)—O—C₀₋₆alkyl, or hydroxyC₁₋₆alkyl substituents;

or R₅ and R₆ form ═O;

or R₆ and R₃ form —CH₂— or —O—; and

n is 0, 1, or 2.

In still another embodiment of this one aspect, the compound of thisinvention is represented by Formula (I) or a pharmaceutically acceptablesalt thereof, wherein

Ar is phenyl substituted with —(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl), and thealkyl group- is optionally substituted with 1-3 independent —OH, —CN,halogen, or —CF₃;

R₁ is —C₁₋₆alkyl, optionally substituted with 1-5 substituents; whereineach substituent is independently a halogen, —OH, —CN, —C₁-C₆alkyl,—C(O)(heterocycloC₃₋₆alkyl), —C(O)—O—(C₀₋₆alkyl), —C(O)—O-aryl, alkoxy,cycloalkyloxy, acyl, acyloxy, -cycloC₃₋₆alkyl, heterocycloC₃₋₆alkyl,aryl, heteroaryl, pyridyl N-oxide, carbonyl, carbamoyl, or—SO_(n)—(C₁₋₆alkyl);

R₂ and R₃ are each hydrogen;

R₄ is hydrogen;

R5 is hydrogen, hydroxyl, —CN; or a C₁₋₆alkyl, —C(O)C₁₋₆alkyl,—C(O)-aryl, —C(O)-pyridyl, —C(O)—O—C₀₋₆alkyl, —C(O)—C₃₋₇cycloalkyl,—C₁₋₆alkyl-C₃₋₇cycloalkyl, —C₁₋₆alkyl(C₃₋₇cycloalkyl)₂, —C₁₋₆alkyl-aryl,—C(O)—N(C₀₋₆alkyl)₂, —SO_(n)aryl, —SO_(n)—C₁₋₆alkyl,—SO_(n)—C₃₋₇cycloalkyl, —SO_(n)—N(C₀₋₆alkyl)₂, —P(O)(C₁₋₆alkyl)₂,—P(O)(C₁₋₆alkoxy)₂, phenyl, pyridyl, —SO_(n)imidazolyl,—SO_(n)thiazolyl, 5-membered heteroaryl ring containing 1-4 heteroatomsindependently selected from O, S or N group or oxoisoxaphosphinanylgroup, any of which group optionally substituted with 1-6 independenthalogen, hydroxyl, —CN, —CF₃, —C₁₋₆alkyl, —SO_(n)—C₁₋₆alkyl,—C(O)—O—C₀₋₆alkyl, or hydroxyC₁₋₆alkyl substituents;

R₆, and R₇ are each independently hydrogen, halogen, hydroxyl,—C₁₋₆alkyl, or —C₁₋₆alkoxy, wherein the alkyl and alkoxy are optionallysubstituted with 1-3 independently halogen or hydroxyl;

or R₅ and R₆ form ═O;

or R₆ and R₃ form CH₂— or —O—; and

n is 0, 1, or 2.

In a second aspect of the invention, the compound of this invention isrepresented by Formula (1) or a pharmaceutically acceptable saltthereof, wherein

Ar is pyridyl, or pyridyl N-oxide, optionally substituted with 1-3independent —C₁₋₆alkyl, —OH, —CN, halogen, —CF₃,—(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl), —(C₀₋₆alkyl)-SO_(n)—NH—(C₁₋₆alkyl) or5-membered heteroaryl ring containing 1-4 heteroatoms independentlyselected from O, S or N, wherein the 5-membered-ring is optionallysubstituted with C₁₋₆alkyl, and the alkyl group- is optionallysubstituted with 1-3 independent —OH, —CN, halogen, or —CF₃;

R₁ is hydrogen, halogen; or a —C₁₋₆alkyl, -cycloC₃₋₆alkyl, —C₁₋₆alkenyl,—C₀₋₄alkyl-C(O)—C₀₋₄alkyl, —C₁₋₆alkoxy, aryl, heteroaryl, —CN,-heterocycloC₃₋₆alkyl, -amino, —C₁₋₆alkylamino,—(C₁₋₆alkyl)(C₁₋₆alkyl)amino, —C₁₋₆alkyl(oxy)C₁₋₆alkyl, —C(O)NH(aryl),—C(O)NH(heteroaryl), —SO_(n)NH(aryl), —SO_(n)NH(heteroaryl),—SO_(n)NH(C₁₋₆alkyl), —C(O)N(C₀₋₆alkyl)(C₀₋₆alkyl),—NH—SO_(n)—(C₁₋₆alkyl), -carbamoyl, —(C₁₋₆alkyl)-O—C(CN)-dialkylamino,or —(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl) group, wherein any of the groups isoptionally substituted with 1-5 substituents; wherein each substituentis independently a halogen, —OH, —CN, —C₁-C₆alkyl,—C(O)(heterocycloC₃₋₆alkyl), —C(O)—O—(C₀₋₆alkyl), —C(O)—O-aryl, alkoxy,cycloalkyloxy, acyl, acyloxy, -cycloC₃₋₆alkyl, heterocycloC₃₋₆alkyl,aryl, heteroaryl, pyridyl N-oxide, carbonyl, carbamoyl, or—SO_(n)—(C₁₋₆alkyl);

R₂, R₃, R₆, and R₇ are each independently hydrogen, halogen, hydroxyl,—C₁₋₆alkyl, or —C₁₋₆alkoxy, wherein the alkyl and alkoxy are optionallysubstituted with 1-3 independently halogen or hydroxyl;

R₄ is hydrogen, halogen, —CN, phenyl, oxadiazolyl, or —C(O)—O—C₀₋₆alkyl,wherein the phenyl, oxadiazolyl, or —C(O)—O—C₀₋₆alkyl is optionallysubstituted with 1-3 independent halogen, CN, CF3, —SO_(n)—C₁₋₆alkyl, orC₁₋₆alkyl substituents, and the alkyl group is optionally substitutedwith OH;

R5 is hydrogen, hydroxyl, —CN; or a —C₁₋₆alkyl, —C(O)C₁₋₆alkyl,—C(O)-aryl, —C(O)-pyridyl, —C(O)—O—C₀₋₆alkyl, —C(O)—C₃₋₇cycloalkyl,—C₁₋₆alkyl-C₃₋₇cycloalkyl, —C₁₋₆alkyl(C₃₋₇cycloalkyl)₂, —C₁₋₆alkyl-aryl,—C(O)—N(C₀₋₆alkyl)₂, —SO_(n)aryl, —SO_(n)—C₁₋₆alkyl,—SO_(n)—C₃₋₇cycloalkyl, —SO_(n)—N(C₀₋₆alkyl)₂, —P(O)(C₁₋₆alkyl)₂,—P(O)(C₁₋₆alkoxy)₂, phenyl, pyridyl, —SO_(n)imidazolyl,—SO_(n)thiazolyl, 5-membered heteroaryl ring containing 1-4 heteroatomsindependently selected from O, S or N or oxoisoxaphosphinanyl group, anyof which group optionally substituted with 1-6 independent halogen,hydroxyl, —CN, —CF₃, —C₁₋₆alkyl, —SO_(n)—C₁₋₆alkyl, —C(O)—O—C₀₋₆alkyl,or hydroxyC₁₋₆alkyl substituents;

or R₅ and R₆ form ═O;

or R₆ and R₃ form —CH₂— or —O—; and

n is 0, 1, or 2.

In an embodiment of this one aspect, the compound of this invention isrepresented by Formula (I) or a pharmaceutically acceptable saltthereof, wherein

Ar is pyridyl, or pyridyl N-oxide, optionally substituted with 1-3independent —C₁₋₆alkyl, —OH, —CN, halogen, —CF₃,—(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl), —(C₀₋₆alkyl)-SO_(n)—NH—(C₁₋₆alkyl) or5-membered heteroaryl ring containing 1-4 heteroatoms independentlyselected from O, S or N, wherein the 5-membered-ring is optionallysubstituted with C₁₋₆alkyl, and the alkyl group- is optionallysubstituted with 1-3 independent —OH, —CN, halogen, or —CF₃;

R₁ is hydrogen, halogen; or a —C₁₋₆alkyl, -cycloC₃₋₆alkyl, —C₁₋₆alkenyl,—C₀₋₄alkyl-C(O)—C₀₋₄alkyl, —C₁₋₆alkoxy, aryl, heteroaryl, —CN,-heterocycloC₃₋₆alkyl, -amino, —C₁₋₆alkylamino,—(C₁₋₆alkyl)(C₁₋₆alkyl)amino, —C₁₋₆alkyl(oxy)C₁₋₆alkyl, —C(O)NH(aryl),—C(O)NH(heteroaryl), —SO_(n)NH(aryl), —SO_(n)NH(heteroaryl),—SO_(n)NH(C₁₋₆alkyl), —C(O)N(C₀₋₆alkyl)(C₀₋₆alkyl),—NH—SO_(n)—(C₁₋₆alkyl), -carbamoyl, —(C₁₋₆alkyl)-O—C(CN)-dialkylamino,or —(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl) group, wherein any of the groups isoptionally substituted with 1-5 substituents; wherein each substituentis independently a halogen, —OH, —CN, —C₁-C₁₋₆alkyl,—C(O)(heterocycloC₃₋₆alkyl), —C(O)—O—(C₀₋₆alkyl), —C(O)—O-aryl, alkoxy,cycloalkyloxy, acyl, acyloxy, -cycloC₃₋₆alkyl, heterocycloC₃₋₆alkyl,aryl, heteroaryl, pyridyl N-oxide, carbonyl, carbamoyl, or—SO_(n)—(C₁₋₆alkyl);

R₂, R₃, R₆, and R₇ are each independently hydrogen, halogen, hydroxyl,—C₁₋₆alkyl, or —C₁₋₆alkoxy, wherein the alkyl and alkoxy are optionallysubstituted with 1-3 independently halogen or hydroxyl;

R₄ is phenyl optionally substituted with 1-3 independent halogen, CN,CF₃, —SO_(n)—C₁₋₆alkyl, or C₁₋₆alkyl substituents, and the alkyl groupis optionally substituted with OH;

R5 is hydrogen, hydroxyl, —CN; or a —C₁₋₆alkyl, —C(O)C₁₋₆alkyl,—C(O)-aryl, —C(O)-pyridyl, —C(O)—O—C₀₋₆alkyl, —C(O)—C₃₋₇cycloalkyl,—C₁₋₆alkyl-C₃₋₇cycloalkyl, —C₁₋₆alkyl(C₃₋₇cycloalkyl)₂, —C₁₋₆alkyl-aryl,—C(O)—N(C₀₋₆alkyl)₂, —SO_(n)aryl, —SO_(n)—C₁₋₆alkyl,—SO_(n)—C₃₋₇cycloalkyl, —SO_(n)—N(C₀₋₆alkyl)₂, —P(O)(C₁₋₆alkyl)₂,—P(O)(C₁₋₆alkoxy)₂, phenyl, pyridyl, —SO_(n)imidazolyl,—SO_(n)thiazolyl, 5-membered heteroaryl ring containing 1-4 heteroatomsindependently selected from O, S or N or oxoisoxaphosphinanyl group, anyof which group optionally substituted with 1-6 independent halogen,hydroxyl, —CN, —CF₃, —C₁₋₆alkyl, —SO_(n)—C₁₋₆alkyl, —C(O)—O—C₀₋₆alkyl,or hydroxyC₁₋₆alkyl substituents;

or R₅ and R₆ form ═O;

or R₆ and R₃ form —CH₂— or —O—; and

n is 0, 1, or 2.

In another embodiment of this one aspect, the compound of this inventionis represented by Formula (I) or a pharmaceutically acceptable saltthereof, wherein

Ar is pyridyl, or pyridyl N-oxide, optionally substituted with 1-3independent —C₁₋₆alkyl, —OH, —CN, halogen, —CF₃,—(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl), —(C₀₋₆alkyl)-SO_(n)—NH—(C₁₋₆alkyl) or5-membered heteroaryl ring containing 1-4 heteroatoms independentlyselected from O, S or N, wherein the 5-membered-ring is optionallysubstituted with C₁₋₆alkyl, and the alkyl group- is optionallysubstituted with 1-3 independent —OH, —CN, halogen, or —CF₃;

R₁ is hydrogen, halogen; or a —C₁₋₆alkyl, -cycloC₃₋₆alkyl, —C₁₋₆alkenyl,—C₀₋₄alkyl-C(O)—C₀₋₄alkyl, —C₁₋₆alkoxy, aryl, heteroaryl, —CN,-heterocycloC₃₋₆alkyl, -amino, —C₁₋₆alkylamino,—(C₁₋₆alkyl)(C₁₋₆alkyl)amino, —C₁₋₆alkyl(oxy)C₁₋₆alkyl, —C(O)NH(aryl),—C(O)NH(heteroaryl), —SO_(n)NH(aryl), —SO_(n)NH(heteroaryl),—SO_(n)NH(C₁₋₆alkyl), —C(O)N(C₀₋₆alkyl)(C₀₋₆alkyl),—NH—SO_(n)—(C₁₋₆alkyl), -carbamoyl, —(C₁₋₆alkyl)-O—C(CN)-dialkylamino,or —(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl) group, wherein any of the groups isoptionally substituted with 1-5 substituents; wherein each substituentis independently a halogen, —H, —CN, —C₁-C₆alkyl,—C(O)(heterocycloC₃₋₆alkyl), —C(O)—O—(C₀₋₆alkyl), —C(O)—O-aryl, alkoxy,cycloalkyloxy, acyl, acyloxy, -cycloC₃₋₆alkyl, heterocycloC₃₋₆alkyl,aryl, heteroaryl, pyridyl N-oxide, carbonyl, carbamoyl, or—SO_(n)—(C₁₋₆alkyl);

R₂, R₃, R₆, and R₇ are each independently hydrogen, halogen, hydroxyl,—C₁₋₆alkyl, or —C₁₋₆alkoxy, wherein the alkyl and alkoxy are optionallysubstituted with 1-3 independently halogen or hydroxyl;

R₄ is hydrogen, halogen, —CN, or —C(O)—O—C₀₋₆alkyl, wherein the phenyl,oxadiazolyl, or —C(O)—O—C₀₋₆alkyl is optionally substituted with 1-3independent halogen, CN, CF3, —SO_(n)—C₁₋₆alkyl, or C₁₋₆alkylsubstituents, and the alkyl group is optionally substituted with OH;

R5 is hydrogen, hydroxyl, —CN; or a —C₁₋₆alkyl, —C(O)C₁₋₆alkyl,—C(O)-aryl, —C(O)-pyridyl, —C(O)—O—C₀₋₆alkyl, —C(O)—C₃₋₇cycloalkyl,—C₁₋₆alkyl-C₃₋₇cycloalkyl, —C₁₋₆alkyl(C₃₋₇cycloalkyl)₂, —C₁₋₆alkyl-aryl,—C(O)—N(C₀₋₆alkyl)₂, —SO_(n)aryl, —SO_(n)—C₁₋₆alkyl,—SO_(n)—C₃₋₇cycloalkyl, —SO_(n)—N(C₀₋₆alkyl)₂, —P(O)(C₁₋₆alkyl)₂,—P(O)(C₁₋₆alkoxy)₂, phenyl, pyridyl, —SO_(n)imidazolyl,—SO_(n)thiazolyl, 5-membered heteroaryl ring containing 1-4 heteroatomsindependently selected from O, S or N or oxoisoxaphosphinanyl group, anyof which group optionally substituted with 1-6 independent halogen,hydroxyl, —CN, —CF3, —C₁₋₆alkyl, —SO_(n)—C₁₋₆alkyl, —C(O)—O—C₀₋₆alkyl,or hydroxyC₁₋₆alkyl substituents;

or R₅ and R₆ form ═O;

or R₆ and R₃ form CH₂— or —O—; and

n is 0, 1, or 2.

In another embodiment of this one aspect, the compound of this inventionis represented by Formula (I) or a pharmaceutically acceptable saltthereof, wherein

Ar is pyridyl, or pyridyl N-oxide, optionally substituted with 1-3independent —C₁₋₆alkyl, —OH, —CN, halogen, —CF₃,—(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl), —(C₀₋₆alkyl)-SO_(n)—NH—(C₁₋₆alkyl) or5-membered heteroaryl ring containing 1-4 heteroatoms independentlyselected from O, S or N, wherein the 5-membered-ring is optionallysubstituted with C₁₋₆alkyl, and the alkyl group- is optionallysubstituted with 1-3 independent —OH, —CN, halogen, or —CF₃;

R₁ is hydrogen, halogen; or a —C₁₋₆alkyl, -cycloC₃₋₆alkyl, —C₁₋₆alkenyl,—C₀₋₄alkyl-C(O)—C₀₋₄alkyl, —C₁₋₆alkoxy, aryl, heteroaryl, —CN,-heterocycloC₃₋₆alkyl, -amino, —C₁₋₆alkylamino,—(C₁₋₆alkyl)(C₁₋₆alkyl)amino, —C₁₋₆alkyl(oxy)C₁₋₆alkyl, —C(O)NH(aryl),—C(O)NH(heteroaryl), —SO_(n)NH(aryl); —SO_(n)NH(heteroaryl),—SO_(n)NH(C₁₋₆alkyl), —C(O)N(C₀₋₆alkyl)(C₀₋₆alkyl),—NH—SO_(n)—(C₁₋₆alkyl), -carbamoyl, —(C₁₋₆alkyl)-O—C(CN)-dialkylamino,or —(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl) group, wherein any of the groups isoptionally substituted with 1-5 substituents; wherein each substituentis independently a halogen, —OH, —CN, —C₁-C₆alkyl,—C(O)(heterocycloC₃₋₆alkyl), —C(O)—O—(C₀₋₆alkyl), —C(O)—O-aryl, alkoxy,cycloalkyloxy, acyl, acyloxy, -cycloC₃₋₆alkyl, heterocycloC₃₋₆alkyl,aryl, heteroaryl, pyridyl N-oxide, carbonyl, carbamoyl, or—SO_(n)—(C₁₋₆alkyl);

R₂, R₃, R₆, and R₇ are each independently hydrogen, halogen, hydroxyl,—C₁₋₆alkyl, or —C₁₋₆alkoxy, wherein the alkyl and alkoxy are optionallysubstituted with 1-3 independently halogen or hydroxyl;

R₄ is hydrogen, halogen, —CN, phenyl, oxadiazolyl, or —C(O)—O—C₀₋₆alkyl,wherein the phenyl, oxadiazolyl, or —C(O)—O—C₀₋₆alkyl is optionallysubstituted with 1-3 independent halogen, CN, CF3, —SO_(n)—C₁₋₆alkyl, orC₁₋₆alkyl substituents, and the alkyl group is optionally substitutedwith OH;

R5 is hydrogen, hydroxyl, —CN; or a —C₁₋₆alkyl, —C(O)C₁₋₆alkyl,—C(O)-aryl, —C(O)-pyridyl, —C(O)—O—C₀₋₆alkyl, —C(O)—C₃₋₇cycloalkyl,—C₁₋₆alkyl-C₃₋₇cycloalkyl, —C₁₋₆alkyl(C₃₋₇cycloalkyl)₂, —C₁₋₆alkyl-aryl,—C(O)—N(C₀₋₆alkyl)₂, —SO_(n)aryl, —SO_(n)—C₁₋₆alkyl,—SO_(n)—C₃₋₇cycloalkyl, —SO_(n)—N(C₀₋₆alkyl)₂, —P(O)(C₁₋₆alkyl)₂,—P(O)(C₁₋₆alkoxy)₂, phenyl, pyridyl, —SO_(n)imidazolyl,—SO_(n)thiazolyl, 5-membered heteroaryl ring containing 1-4 heteroatomsindependently selected from O, S or N or oxoisoxaphosphinanyl group, anyof which group optionally substituted with 1-6 independent halogen,hydroxyl, —CN, —CF₃, —C₁₋₆alkyl, —SO_(n)—C₁₋₆alkyl, —C(O)—O—C₀₋₆alkyl,or hydroxyC₁₋₆alkyl substituents;

or R₅ and R₆ form ═O;

or R₆ and R₃ form —O—; and

n is 0, 1, or 2.

In another embodiment of this one aspect, the compound of this inventionis represented by Formula (I) or a pharmaceutically acceptable saltthereof, wherein

Ar is pyridyl, or pyridyl N-oxide, optionally substituted with 1-3independent —C₁₋₆alkyl, —OH, —CN, halogen, —CF₃,—(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl), —(C₀₋₆alkyl)-SO_(n)—NH—(C₁₋₆alkyl) or5-membered heteroaryl ring containing 1-4 heteroatoms independentlyselected from O, S or N, wherein the 5-membered-ring is optionallysubstituted with C₁₋₆alkyl, and the alkyl group- is optionallysubstituted with 1-3 independent —OH, —CN, halogen, or —CF₃;

R₁ is —C₁₋₆alkyl or -cycloC₃₋₆alkyl, wherein any of the groups isoptionally substituted with 1-5 substituents; wherein each substituentis independently a halogen, —OH, —CN, —C₁-C₆alkyl,—C(O)(heterocycloC₃₋₆alkyl), —C(O)—O—(C₀₋₆alkyl), —C(O)—O-aryl, alkoxy,cycloalkyloxy, acyl, acyloxy, -cycloC₃₋₆alkyl, heterocycloC₃₋₆alkyl,aryl, heteroaryl, pyridyl N-oxide, carbonyl, carbamoyl, or—SO_(n)—(C₁₋₆alkyl);

R₂, R₃, R₆, and R₇ are each independently hydrogen, halogen, hydroxyl,—C₁₋₆alkyl, or —C₁₋₆alkoxy, wherein the alkyl and alkoxy are optionallysubstituted with 1-3 independently halogen or hydroxyl;

R₄ is hydrogen, halogen, —CN, phenyl, oxadiazolyl, or —C(O)—O—C₀₋₆alkyl,wherein the phenyl, oxadiazolyl, or —C(O)—O—C₀₋₆alkyl is optionallysubstituted with 1-3 independent halogen, CN, CF3, —SO_(n)—C₁₋₆alkyl, orC₁₋₆alkyl substituents, and the alkyl group is optionally substitutedwith OH;

R5 is hydrogen, hydroxyl, —CN; or a —C₁₋₆alkyl, —C(O)C₁₋₆alkyl,—C(O)-aryl, —C(O)-pyridyl, —C(O)—O—C₀₋₆alkyl, —C(O)—C₃₋₇cycloalkyl,—C₁₋₆alkyl-C₃₋₇cycloalkyl, —C₁₋₆alkyl(C₃₋₇cycloalkyl)₂, —C₁₋₆alkyl-aryl,—C(O)—N(C₀₋₆alkyl)₂, —SO_(n)aryl, —SO_(n)—C₁₋₆alkyl,—SO_(n)—C₃₋₇cycloalkyl, —SO_(n)—N(C₀₋₆alkyl)₂, —P(O)(C₁₋₆alkyl)₂,—P(O)(C₁₋₆alkoxy)₂, phenyl, pyridyl, —SO_(n)imidazolyl,—SO_(n)thiazolyl, 5-membered heteroaryl ring containing 1-4 heteroatomsindependently selected from O, S or N or oxoisoxaphosphinanyl group, anyof which group optionally substituted with 1-6 independent halogen,hydroxyl, —CN, —CF₃, —C₁₋₆alkyl, —SO_(n)—C₁₋₆alkyl, —C(O)—O—C₀₋₆alkyl,or hydroxyC₁₋₆alkyl substituents;

or R₅ and R₆ form ═O;

or R₆ and R₃ form —CH₂— or —O—; and

n is 0, 1, or 2.

In another embodiment of this one aspect, the compound of this inventionis represented by Formula (I) or a pharmaceutically acceptable saltthereof, wherein

Ar is pyridyl, or pyridyl N-oxide, optionally substituted with 1-3independent —C₁₋₆alkyl, —OH, —CN, halogen, —CF₃,—(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl), —(C₀₋₆alkyl)-SO_(n)—NH—(C₁₋₆alkyl) or5-membered heteroaryl ring containing 1-4 heteroatoms independentlyselected from O, S or N, wherein the 5-membered-ring is optionallysubstituted with C₁₋₆alkyl, and the alkyl group- is optionallysubstituted with 1-3 independent —OH, —CN, halogen, or —CF₃;

R₁ is —C₁₋₆alkyl, -cycloC₃₋₆alkyl, wherein any of the groups isoptionally substituted with 1-5 substituents; wherein each substituentis independently a halogen, —OH, —CN, —C₁-C₆alkyl,—C(O)(heterocycloC₃₋₆alkyl), —C(O)—O—(C₀₋₆alkyl), —C(O)—O-aryl, alkoxy,cycloalkyloxy, acyl, acyloxy, -cycloC₃₋₆alkyl, heterocycloC₃₋₆alkyl,aryl, heteroaryl, pyridyl N-oxide, carbonyl, carbamoyl, or—SO_(n)—(C₁₋₆alkyl);

R₂, R₃, R₆, and R₇ are each independently hydrogen, halogen, hydroxyl,—C₁₋₆alkyl, or —C₁₋₆alkoxy, wherein the alkyl and alkoxy are optionallysubstituted with 1-3 independently halogen or hydroxyl;

R₄ is hydrogen, halogen, —CN, or —C(O)—O—C₀₋₆alkyl, wherein the—C(O)—O—C₀₋₆alkyl is optionally substituted with 1-3 independenthalogen, CN, CF₃, —SO_(n)—C₁₋₆alkyl, or C₁₋₆alkyl substituents, and thealkyl group is optionally substituted with OH

R5 is hydrogen, hydroxyl, —CN; or a —C₁₋₆alkyl, —C(O)C₁₋₆alkyl,—C(O)-aryl, —C(O)-pyridyl, —C(O)—O—C₀₋₆alkyl, —C(O)—C₃₋₇cycloalkyl,—C₁₋₆alkyl-C₃₋₇cycloalkyl, —C₁₋₆alkyl(C₃₋₇cycloalkyl)₂, —C₁₋₆alkyl-aryl,—C(O)—N(C₀₋₆alkyl)₂, —SO_(n)aryl, —SO_(n)—C₁₋₆alkyl,—SO_(n)—C₃₋₇cycloalkyl, —SO_(n)—N(C₀₋₆alkyl)₂, —P(O)(C₁₋₆alkyl)₂,—P(O)(C₁₋₆alkoxy)₂, phenyl, pyridyl, —SO_(n)imidazolyl,—SO_(n)thiazolyl, 5-membered heteroaryl ring containing 1-4 heteroatomsindependently selected from O, S or N or oxoisoxaphosphinanyl group, anyof which group optionally substituted with 1-6 independent halogen,hydroxyl, —CN, —CF3, —C₁₋₆alkyl, —SO_(n)—C₁₋₆alkyl, —C(O)—O—C₀₋₆alkyl,or hydroxyC₁₋₆alkyl substituents;

or R₅ and R₆ form ═O;

or R₆ and R₃ form —CH₂— or —O—; and

n is 0, 1, or 2.

In another embodiment of this one aspect, the compound of this inventionis represented by Formula (I) or a pharmaceutically acceptable saltthereof, wherein

Ar is pyridyl, or pyridyl N-oxide, optionally substituted with 1-3independent —C₁₋₆alkyl, —OH, —CN, halogen, —CF₃,—(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl), —(C₀₋₆alkyl)-SO_(n)—NH—(C₁₋₆alkyl) or5-membered heteroaryl ring containing 1-4 heteroatoms independentlyselected from O, S or N, wherein the 5-membered-ring is optionallysubstituted with C₁₋₆alkyl, and the alkyl group- is optionallysubstituted with 1-3 independent —OH, —CN, halogen, or —CF₃;

R₁ is —C₁₋₆alkyl, -cycloC₃₋₆alkyl, wherein any of the groups isoptionally substituted with 1-5 substituents; wherein each substituentis independently a halogen, —OH, —CN, —C₁-C₆alkyl,—C(O)(heterocycloC₃₋₆alkyl), —C(O)—O—(C₀₋₆alkyl), —C(O)—O-aryl, alkoxy,cycloalkyloxy, acyl, acyloxy, -cycloC₃₋₆alkyl, heterocycloC₃₋₆alkyl,aryl, heteroaryl, pyridyl N-oxide, carbonyl, carbamoyl, or—SO_(n)(C₁₋₆alkyl);

R₂, R₃, R₆, and R₇ are each independently hydrogen, halogen, hydroxyl,—C₁₋₆alkyl, or —C₆alkoxy, wherein the alkyl and alkoxy are optionallysubstituted with 1-3 independently halogen or hydroxyl;

R₄ is hydrogen, halogen, —CN, phenyl, oxadiazolyl, or —C(O)—O—C₀₋₆alkyl,wherein the phenyl, oxadiazolyl, or —C(O)—O—C₀₋₆alkyl is optionallysubstituted with 1-3 independent halogen, CN, CF3, —SO_(n)—C₁₋₆alkyl, orC₁₋₆alkyl substituents, and the alkyl group is optionally substitutedwith OH

R5 is phenyl, pyridyl, or a 5-membered heteroaryl ring containing 1-4heteroatoms independently selected from O, S or N, any of which groupoptionally substituted with 1-6 independent halogen, hydroxyl, —CN,—CF3, —C₁₋₆alkyl, —SO_(n)—C₁₋₆alkyl, —C(O)—O—C₀₋₆alkyl, orhydroxyC₁₋₆alkyl substituents;

or R₅ and R₆ form ═O;

or R₆ and R₃ form —CH₂— or —O—; and

n is 0, 1, or 2.

As used herein, “alkyl” as well as other groups having the prefix “alk”such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like,means carbon chains which may be linear or branched or combinationsthereof. Examples of alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and thelike. “Alkenyl”, “alkynyl” and other like terms include carbon chainscontaining at least one unsaturated C—C bond.

The term “cycloalkyl” means carbocycles containing no heteroatoms, andincludes mono-, bi- and tricyclic saturated carbocycles, as well asfused ring systems. Such fused ring systems can include one ring that ispartially or fully unsaturated such as a benzene ring to form fused ringsystems such as benzofused carbocycles. Cycloalkyl includes such fusedring systems as spirofused ring systems. Examples of cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene,adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphalene andthe like. Similarly, “cycloalkenyl” means carbocycles containing noheteroatoms and at least one non-aromatic C—C double bond, and includemono-, bi- and tricyclic partially saturated carbocycles, as well asbenzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl,indenyl, and the like.

The term “aryl” means an aromatic subsituent which is a single ring ormultiple rings fused together. When formed of multiple rings, at leastone of the constituent rings is aromatic. The preferred arylsubstituents are phenyl and napthyl groups.

The term “cycloalkyloxy” unless specifically stated otherwise includes acycloalkyl group connected by a short C₁₋₂alkyl length to the oxyconnecting atom.

The term “C₀₋₆alkyl” includes alkyls containing 6, 5, 4, 3, 2, 1, or nocarbon atoms. An alkyl with no carbon atoms is a hydrogen atomsubstituent when the alkyl is a terminal group and is a direct bond whenthe alkyl is a bridging group.

The term “hetero” unless specifically stated otherwise includes one ormore O, S, or N atoms. For example, heterocycloalkyl and heteroarylinclude ring systems that contain one or more O, S, or N atoms in thering, including mixtures of such atoms. The hetero atoms replace ringcarbon atoms. Thus, for example, a heterocycloC₅alkyl is a five memberring containing from 5 to no carbon atoms. Examples of heteroarylsinclude pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl,pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl,benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl,oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl. Examples ofheterocycloalkyls include azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl,pyrolidin-2-one, piperidin-2-one, and thiomorpholinyl.

The term “amine” unless specifically stated otherwise includes primary,secondary and tertiary amines.

The term “halogen” includes fluorine, chlorine, bromine and iodineatoms.

The term “optionally substituted” is intended to include bothsubstituted and unsubstituted. Thus, for example, optionally substitutedaryl could represent a pentafluorophenyl or a phenyl ring. Further,optionally substituted multiple moieties such as, for example, alkylarylare intended to mean that the aryl and the aryl groups are optionallysubstituted. If only one of the multiple moieties is optionallysubstituted then it will be specifically recited such as “an alkylaryl,the aryl optionally substituted with halogen or hydroxyl.”

Compounds described herein contain one or more double bonds and may thusgive rise to cis/trans isomers as well as other conformational isomers.The present invention includes all such possible isomers as well asmixtures of such isomers.

Compounds described herein can contain one or more asymmetric centersand may thus give rise to diastereomers and optical isomers. The presentinvention includes all such possible diastereomers as well as theirracemic mixtures, their substantially pure resolved enantiomers, allpossible geometric isomers, and pharmaceutically acceptable saltsthereof. The above Formula I is shown without a definitivestereochemistry at certain positions. The present invention includes allstereoisomers of Formula I and pharmaceutically acceptable saltsthereof. Further, mixtures of stereoisomers as well as isolated specificstereoisomers are also included. During the course of the syntheticprocedures used to prepare such compounds, or in using racemization orepimerization procedures known to those skilled in the art, the productsof such procedures can be a mixture of stereoisomers.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Particularly preferred arethe ammonium, calcium, magnesium, potassium and sodium salts. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, as well as cyclicamines and substituted amines such as naturally occurring andsynthesized substituted amines. Other pharmaceutically acceptableorganic non-toxic bases from which salts can be formed include ionexchange resins such as, for example, arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.Particularly preferred are citric, hydrobromic, hydrochloric, maleic,phosphoric, sulfuric, and tartaric acids.

The pharmaceutical compositions of the present invention comprise acompound represented by Formula I (or pharmaceutically acceptable saltsthereof) as an active ingredient, a pharmaceutically acceptable carrierand optionally other therapeutic ingredients or adjuvants. Suchadditional therapeutic ingredients include, for example, i) Leukotrienereceptor antagonists, ii) Leukotriene biosynthesis inhibitors, iii)corticosteroids, iv) H1 receptor antagonists, v) beta 2 adrenoceptoragonists, vi) COX-2 selective inhibitors, vii) statins, viii)non-steroidal anti-inflammatory drugs (“NSAID”), and ix) M2/M3antagonists. The compositions include compositions suitable for oral,rectal, topical, and parenteral (including subcutaneous, intramuscular,and intravenous) administration, although the most suitable route in anygiven case will depend on the particular host, and nature and severityof the conditions for which the active ingredient is being administered.The pharmaceutical compositions may be conveniently presented in unitdosage form and prepared by any of the methods well known in the art ofpharmacy.

Creams, ointments, jellies, solutions, or suspensions containing thecompound of Formula I can be employed for topical use. Mouth washes andgargles are included within the scope of topical use for the purposes ofthis invention.

Dosage levels from about 0.01 mg/kg to about 140 mg/kg of body weightper day are useful in the treatment of conditions such as asthma,chronic bronchitis, chronic obstructive pulmonary disease (COPD),eosinophilic granuloma, psoriasis and other benign or malignantproliferative skin diseases, endotoxic shock (and associated conditionssuch as laminitis and colic in horses), septic shock, ulcerativecolitis, Crohn's disease, reperfusion injury of the myocardium andbrain, inflammatory arthritis, chronic glomerulonephritis, atopicdermatitis, urticaria, adult respiratory distress syndrome, chronicobstructive pulmonary disease in animals, diabetes insipidus, allergicrhinitis, allergic conjunctivitis, vernal conjunctivitis, arterialrestenosis, ortherosclerosis, atherosclerosis, neurogenic inflammation,pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplantrejection and graft versus host disease, hypersecretion of gastric acid,bacterial, fungal or viral induced sepsis or septic shock, inflammationand cytokine-mediated chronic tissue degeneration, osteoarthritis,cancer, cachexia, muscle wasting, depression, memory impairment, tumourgrowth and cancerous invasion of normal tissues which are responsive toPDE4 inhibition, or alternatively about 0.5 mg to about 7 g per patientper day. For example, inflammation may be effectively treated by theadministration of from about 0.01 mg to 50 mg of the compound perkilogram of body weight per day, or alternatively about 0.5 mg to about3.5 g per patient per day. Further, it is understood that the PDE4inhibiting compounds of this invention can be administered atprophylactically effective dosage levels to prevent the above-recitedconditions.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration to humans mayconveniently contain from about 0.5 mg to about 5 g of active agent,compounded with an appropriate and convenient amount of carrier materialwhich may vary from about 5 to about 95 percent of the totalcomposition. Unit dosage forms will generally contain between from about1 mg to about 1000 mg of the active ingredient, typically 25 mg, 50 mg,100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

In practice, the compounds represented by Formula I, or pharmaceuticallyacceptable salts thereof, of this invention can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compound represented byFormula I, or pharmaceutically acceptable salts thereof, may also beadministered by controlled release means and/or delivery devices. Thecompositions may be prepared by any of the methods of pharmacy. Ingeneral, such methods include a step of bringing into association theactive ingredient with the carrier that constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention may include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of Formula I. The compounds of Formula I, orpharmaceutically acceptable salts thereof, can also be included inpharmaceutical compositions in combination with one or more othertherapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media may be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likemay be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like may be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets may be coated by standard aqueous or nonaqueoustechniques

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.1 mg to about 500 mg of theactive ingredient and each cachet or capsule preferably containing fromabout 0.1 mg to about 500 mg of the active ingredient. Thus, a tablet,cachet, or capsule conveniently contains 0.1 mg, 1 mg, 5 mg, 25 mg, 50mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredienttaken one or two tablets, cachets, or capsules, once, twice, or threetimes daily.

Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability.

The pharmaceutical compositions must be stable under the conditions ofmanufacture and storage; thus, preferably should be preserved againstthe contaminating action of microorganisms such as bacteria and fungi.The carrier can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (e.g. glycerol, propylene glycol andliquid polyethylene glycol), vegetable oils, and suitable mixturesthereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared, utilizing a compound represented byFormula I of this invention, or pharmaceutically acceptable saltsthereof, via conventional processing methods. As an example, a cream orointment is prepared by mixing hydrophilic material and water, togetherwith about 5 wt % to about 10 wt % of the compound, to produce a creamor ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in moulds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound described by Formula I, or pharmaceuticallyacceptable salts thereof, may also be prepared in powder or liquidconcentrate form.

The compounds and pharmaceutical compositions of this invention havebeen found to exhibit biological activity as PDE4 inhibitors.Accordingly, another aspect of the invention is the treatment in mammalsof, for example, asthma, chronic bronchitis, chronic obstructivepulmonary disease (COPD), eosinophilic granuloma, psoriasis and otherbenign or malignant proliferative skin diseases, endotoxic shock (andassociated conditions such as laminitis and colic in horses), septicshock, ulcerative colitis, Crohn's disease, reperfusion injury of themyocardium and brain, inflammatory arthritis, chronicglomerulonephritis, atopic dermatitis, urticaria, adult respiratorydistress syndrome, chronic obstructive pulmonary disease in animals,diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernalconjunctivitis, arterial restenosis, ortherosclerosis, atherosclerosis,neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosingspondylitis, transplant rejection and graft versus host disease,hypersecretion of gastric acid, bacterial, fungal or viral inducedsepsis or septic shock, inflammation and cytokine-mediated chronictissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting,depression, memory impairment, tumour growth and cancerous invasion ofnormal tissues—maladies that are amenable to amelioration throughinhibition of the PDE4 isoenzyme and the resulting elevated cCAMPlevels—by the administration of an effective amount of the compounds ofthis invention. The term “mammals” includes humans, as well as otheranimals such as, for example, dogs, cats, horses, pigs, and cattle.Accordingly, it is understood that the treatment of mammals other thanhumans is the treatment of clinical correlating afflictions to thoseabove recited examples that are human afflictions.

Further, as described above, the compound of this invention can beutilized in combination with other therapeutic compounds. In particular,the combinations of the PDE4 inhibiting compound of this invention canbe advantageously used in combination with i) Leukotriene receptorantagonists, ii) Leukotriene biosynthesis inhibitors, or iii) M2/M3antagonists.

The abbreviations used herein have the following tabulated meanings.Abbreviations not tabulated below have their meanings as commonly usedunless specifically stated otherwise.

Ac acetyl AIBN 2,2′-azobis(isobutyronitrile) BINAP 1,1′-bi-2-naphthol Bnbenzyl CAMP cyclic adenosine-3′,5′-monophosphate DAST(diethylamino)sulfur trifluoride DEAD diethyl azodicarboxylate DBU1,8-diazabicyclo[5.4.0]undec-7-ene DIBAL diisobutylaluminum hydride DMAP4-(dimethylamino)pyridine DMF N,N-dimethylformamide dppf1,1′-bis(diphenylphosphino)-ferrocene EDCI1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Et₃Ntriethylamine GST glutathione transferase HMDS hexamethyldisilazide LDAlithium diisopropylamide m-CPBA metachloroperbenzoic acid MMPPmonoperoxyphthalic acid MPPM monoperoxyphthalic acid, magnesium salt6H₂O Ms methanesulfonyl = mesyl = SO₂Me Ms0 methanesulfonate = mesylateNBS N-bromo succinimide NSAID non-steroidal anti-inflammatory drug o-Tolortho-tolyl OXONE ® 2KHSO₅.KHSO₄.K2SO₄ PCC pyridinium chlorochromatePd₂(dba)₃ Bis(dibenzylideneacetone)palladium(0) PDC pyridiniumdichromate PDE Phosphodiesterase Ph Phenyl Phe Benzenediyl PMBpara-methoxybenzyl Pye Pyridinediyl r.t. room temperature Rac. RacemicSAM aminosulfonyl or sulfonamide or SO₂NH₂ SEM2-(trimethylsilyl)ethoxymethoxy SPA scintillation proximity assay TBAFtetra-n-butylammonium fluoride Th 2- or 3-thienyl TFA trifluoroaceticacid TFAA trifluoroacetic acid anhydride THF Tetrahydrofuran ThiThiophenediyl TLC thin layer chromatography TMS-CN trimethylsilylcyanide TMSI trimethylsilyl iodide Tz 1H (or 2H)-tetrazol-5-yl XANTPHOS4,5-Bis-diphenylphosphanyl-9,9-dimethyl-9H- xanthene C₃H₅ AllylAlkyl Group Abbreviations

Me = Methyl Et = ethyl n-Pr = normal propyl i-Pr = isopropyl n-Bu =normal butyl i-Bu = isobutyl s-Eu = secondary butyl t-Bu = tertiarybutyl c-Pr = cyclopropyl c-Bu = cyclobutyl c-Pen = cyclopentyl c-Hex =cyclohexyl

Assays Demonstrating Biological Activity LPS and FMLP-Induced TNF-α andLTB₄ Assays in Human Whole Blood

Whole blood provides a protein and cell-rich milieu appropriate for thestudy of biochemical efficacy of anti-inflammatory compounds such asPDE4-selective inhibitors. Normal non-stimulated human blood does notcontain detectable levels of TNF-α and LTB₄. Upon stimulation with LPS,activated monocytes express and secrete TNF-α up to 8 hours and plasmalevels remain stable for 24 hours. Published studies have shown thatinhibition of TNF-α by increasing intracellular cAMP via PDE4 inhibitionand/or enhanced adenylyl cyclase activity occurs at the transcriptionallevel. LTB₄ synthesis is also sensitive to levels of intracellular cAMPand can be completely inhibited by PDE4-selective inhibitors. As thereis little LTB₄ produced during a 24 hour LPS stimulation of whole blood,an additional LPS stimulation followed by tMTP challenge of human wholeblood is necessary for LTB₄ synthesis by activated neutrophils. Thus, byusing the same blood sample, it is possible to evaluate the potency of acompound on two surrogate markers of PDE4 activity in the whole blood bythe following procedure.

Fresh blood was collected in heparinized tubes by venipuncture fromhealthy human volunteers (male and female). These subjects had noapparent inflammatory conditions and had not taken any NSAIDs for atleast 4 days prior to blood collection. 500 μL aliquots of blood werepre-incubated with either 2 μL of vehicle (DMSO) or 2 μL of testcompound at varying concentrations for 15 minutes at 37° C. This wasfollowed by the addition of either 10 μL vehicle (PBS) as blanks or 10μL LPS (1 μg/mL final concentration, #L-2630 (Sigma Chemical Co., St.Louis, Mo.) from E. coli, serotype 0111:B4; diluted in 0.1% w/v BSA (inPBS)). After 24 hours of incubation at 37° C., another 10 μL of PBS(blank) or 10 μL of LPS (1 μg/mL final concentration) was added to bloodand incubated for 30 minutes at 37° C. The blood was then challengedwith either 10 μL of PBS (blank) or 10 μL of fMLP (1 μM finalconcentration, #F-3506 (Sigma); diluted in 1% w/v BSA (in PBS)) for 15minutes at 37° C. The blood samples were centrifuged at 1500×g for 10minutes at 4° C. to obtain plasma. A 50 μL aliquot of plasma was mixedwith 200 μL methanol for protein precipitation and centrifuged as above.The supernatant was assayed for LTB₄ using an enzyme immunoassay kit(#520111 from Cayman Chemical Co., Ann Arbor, Mich.) according to themanufacturer's procedure. TNF-α was assayed in diluted plasma (in PBS)using an ELISA kit (Cistron Biotechnology, Pine Brook, N.J.) accordingto manufacturer's procedure. The IC₅₀ values of Examples 1-113 generallyranged from 0.02 μM to 26 μM.

Anti-allergic Activity In Vivo

Compounds of the invention have been tested for effects on anIgE-mediated allergic pulmonary inflammation induced by inhalation ofantigen by sensitized guinea pigs. Guinea pigs were initially sensitizedto ovalbumin under mild cyclophosphamide-induced immunosuppression, byintraperitoneal injection of antigen in combinations with aluminumhydroxide and pertussis vaccine. Booster doses of antigen were given twoand four weeks later. At six weeks, animals were challenged withaerosolized ovalbumin while under cover of an intraperitoneallyadministered anti-histamine agent (mepyramine). After a further 48 h,bronchial alveolar lavages (BAL) were performed and the numbers ofeosinophils and other leukocytes in the BAL fluids were counted. Thelungs were also removed for histological examination for inflammatorydamage. Administration of compounds of the Examples (0.001-10 mg/kg i.p.or p.o.), up to three times during the 48 h following antigen challenge,lead to a significant reduction in the eosinophilia and the accumulationof other inflammatory leukocytes. There was also less inflammatorydamage in the lungs of animals treated with compounds of the Examples.

SPA Based PDE Activity Assay Protocol

Compounds which inhibit the hydrolysis of cAMP to AMP by the type-IVcAMP-specific phosphodiesterases were screened in a 96-well plate formatas follows:

In a 96 well-plate at 30° C. was added the test compound (dissolved in 2μL DMSO), 188 mL of substrate buffer containing [2,8-³H] adenosine3′,5′-cyclic phosphate (cAMP, 100 nM to 50 μM), 10 mMmgCl₂, 1 mM EDTA,50 mM Tris, pH 7.5. The reaction was initiated by the addition of 10 mLof human recombinant PDE4 (the amount was controlled so that ˜10%product was formed in 10 min.). The reaction was stopped after 10 min.by the addition of 1 mg of PDE-SPA beads (Amersham Pharmacia Biotech,Inc., Piscataway, N.J.). The product AMP generated was quantified on aWallac Microbeta® 96-well plate counter (EG&G Wallac Co., Gaithersburg,Md.). The signal in the absence of enzyme was defined as the background.100% activity was defined as the signal detected in the presence ofenzyme and DMSO with the background subtracted. Percentage of inhibitionwas calculated accordingly. IC₅₀ value was approximated with anon-linear regression fit using the standard 4-parameter/multiplebinding sites equation from a ten point titration.

The IC₅₀ values of Examples 1-113 were determined with 100 nM cAMP usingthe purified GST fusion protein of the human recombinantphosphodiesterase IVa (met-248) produced from a baculovirus/Sf-9expression system. The IC₅₀ values of Examples 1-113 generally rangedfrom 0.1 nM to 25 nM.

The examples that follow are intended as an illustration of certainpreferred embodiments of the invention and no limitation of theinvention is implied.

Unless specifically stated otherwise, the experimental procedures wereperformed under the following conditions. All operations were carriedout at room or ambient temperature—that is, at a temperature in therange of 18-25° C. Evaporation of solvent was carried out using a rotaryevaporator under reduced pressure (600-4000 pascals: 4.5-30 mm. Hg) witha bath temperature of up to 60° C. The course of reactions was followedby thin layer chromatography (TLC) and reaction times are given forillustration only. Melting points are uncorrected and ‘d’ indicatesdecomposition. The melting points given are those obtained for thematerials prepared as described. Polymorphism may result in isolation ofmaterials with different melting points in some preparations. Thestructure and purity of all final products were assured by at least oneof the following techniques: TLC, mass spectrometry, nuclear magneticresonance (NMR) spectrometry or microanalytical data. Yields are givenfor illustration only. When given, NMR data is in the form of delta (δ)values for major diagnostic protons, given in parts per million (ppm)relative to tetramethylsilane (TMS) as internal standard, determined at300 MHz, 400 MHz or 500 MHz using the indicated solvent. Conventionalabbreviations used for signal shape are: s. singlet; d. doublet; t.triplet; m. multiplet; br. broad; etc. In addition, “Ar” signifies anaromatic signal. Chemical symbols have their usual meanings; thefollowing abbreviations have also been used: v (volume), w (weight),b.p. (boiling point), m.p. (melting point), L (liter(s)), mL(milliliters), g (gram(s)), mg (milligrams(s)), mol (moles), mmol(millimoles), eq (equivalent(s)).

Methods of Synthesis

Compounds of the present invention can be prepared according to thefollowing methods. The substituents are the same as in Formula I exceptwhere defined otherwise.

Scheme 1:

Preparation of 8-bromo-quinolines

The quinolines of formula IV may be obtained from literature procedure(R. H. F. Manske and M. Kulka, “The Skraup Synthesis of Quinolines”;Org.

Reaction, vol. 7, p. 59-98, 1953 or in International Patent PublicationWO 94/22852) or prepared in a multi-step sequence from the requisite8-bromo-6-methyl-quinoline II. Treatment of 8-bromo-6-methyl-quinoline(from references cited in text) with brominating agents such as NBS insolvents such as chlorobenzene in presence of radical initiator such asAIBN or benzoyl peroxide provide the 8-bromo-6-bromomethyl-quinoline II.The primary bromide can be displace by nucleophiles such as sodiummethanesulfinate or potassium cyanide in a solvent such as DMF. Twosequential alkylation using alkylating agents such as iodomethane and abase such as potassium t-butoxide in a solvent such as THF can yields8-bromo-quinolines of such as IV.

Scheme 2:Preparation of 8-Aryl-quinolines

The 8-aryl-quinolines of the formula VIII may be prepared by couplingthe 8-bromo-quinoline such as V with appropriately substitutedphenyl-boronic acids or esters such as VII with heating in the presenceof various palladium catalyst such as Pd(Ph₃P)₄ and a base such assodium carbonate in a mixture of solvent such as DME-H₂O. The alcoholVIII X═CH₂OH) may be converted to the bromide by treatment with HBr(aq.) in a solvent such as acetic acid or to the mesylate and then tothe cyanide derivatives using standard organic chemistry protocols.

Scheme 3:Preparation of Phenyl Acetic Acid Derivatives

The phenyl acetic acid derivatives XI may be prepared fromesterification of commercial product such as X using diazomethane forexample or by reduction of alpha-keto analog IX (J. Med. Chem.,24:399(1981)) using hydride such as NaBH₄ in a solvent such as ethanol.The alcohol XI (X═OH) can be transformed into XI (X═F) using DAST (J.Org. Chem., 40:574(1975)) or other commercial equivalents. Sulfur atommay also be oxidized to sulfone by oxidizing agent such as oxone in amixture of solvents such as THF/MeOH/H₂O.

Scheme 4:Preparation of Phenyl Ethanone Derivatives

Phenyl-ethanone intermediate like XX or XV may be prepared fromappropriately substituted aryl bromide and a methylketone using as acatalysis such as Pd₂(dba)₃ with ligands such as xanphos or binap in asolvent like THF with a base such sodium tert-butoxide. Methyl ketonesuch as XIV can be obtained from commercial sources or prepared fromcondensation of ethyl vinyl ether lithium salt onto ketone such as3-pentanone followed by hydrolysis in acidic media. Aryl bromide such asXIII or XVIX can be prepared using standard organic chemistry protocols.Further modifications of phenyl-ethanone such as XV will lead tosubstituted ethanone XVI and XVII by alkylation with alkyl idodide suchas methyl iodide or a fluoride source such as N-fluorobenzenesulfonimide(Synlett, 187, (1991)) and a base such as potassium tert-butoxide.

Scheme 5:Preparation of Sulfonylmethyl-phenyl Derivatives

Sulfonylmethyl phenyl intermediate like XXIV to XXX may be prepared fromappropriately substituted benzyl halide by displacement of halide bynucleophiles such as methanesulfinic acid sodium salt in a solvent suchas DMF. Alternatively, alkyl and aryl thiols can displace the benzylichalide with a base such as cesium carbonate in a solvent such as DMP.Oxidation of sulfide such as XXX with oxidizing agents such as oxonewill lead to sulfone derivatives such as XXVIII. Displacement of thebenzylic halide with sulfur followed by oxidation with Cl₂ for examplewill afford the corresponding sulfonyl chloride such as XXVI. Furthercondensation with nucleophiles such as amines in a solvent likedichloromethane will give sulfonimides such as XVII. Those methylsulfoneXV to XVIII can also be alkylated with a fluoride source such asN-fluorobenzenesulfonimide (Synlett, 187, (1991)) and a base such aspotassium tert-butoxide to give alpha fluoro analogs such as XXIX.

Scheme 6:Preparation of Phosphonylmethyl-phenyl Derivatives

Phosphonylmethyl phenyl intermediate like XXXI to XXXIV may be preparedfrom appropriately substituted benzyl halide by displacement of halideby nucleophiles such as trimethylphosphite. Hydrolysis to phosphonicacid may be accomplished using TMSBr in a solvent such as chloroform.Conversion to the acid chloride using oxalyl chloride for example in asolvent such as dichloromethane will provide the starting material forfurther condensation with nucleophiles such as alcohol in a solvent likedichloromethane and with a base such as triethylamine to give variousphosphonate esters such as XXXIV. The latter can also be alkylated witha fluoride source such as N-fluorobenzenesulfonimide (Synlett, 187,(1991)) and a base such as potassium tert-butoxide to give alpha fluoroanalogs such as XXXII.

Scheme 7:Preparation of Quinoline of Formula I

The quinolines of formula I may be obtained from alkylation of variouscarbonyl containing intermediates from Schemes 3 to 6 (esters, ketones,aldehydes, sulfonyl or phosphonates) with appropriate electrophilederivatives (Scheme 2). For example, the treatment of an intermediate(containing an acidic proton like a ketone etc.) with a base such aspotassium t-butoxide in a organic solvent such THF, followed byquenching with an electrophile such as bromomethyl quinoline VIII,(X═CH₂Br) will give desired product of formula I. Alternatively, thequinoline/electrophile can be reverse to a quinoline/nucleophile andcoupling with aryl halide will afford compounds with a differentsubstitution pattern as described in Scheme 7.

Scheme 8:Preparation of Carboxylic Acid Derived Analogs

Quinoline of formula I containing a carboxylic acid derivative such asXXXV can serve as a starting material for various other analogs asexemplified in Scheme 8. Formation of oxadiazole XXXVII may be achievedby activation of acetic acid XXXVI with EDCI in a solvent such asdiglyme followed by the addition of N-hydroxy-acetamidine and subsequentheating of the reaction mixture. Formation of the acid chloride oractivation of acid by using standard procedures followed by addition ofamines produces amide XXXVIII. Tetrazole like XXXXVI can be obtainedfrom nitrile XXXXV by heating with tributyltin azide in a solvent suchas xylene. All other derivatives described in scheme 8 can be obtainedusing standard organic synthesis procedures related to reduction andaddition of nucleophiles such as lithium or magnesium salts to thecarbonyl functional group. Those standards procedure also includesoxidation of alcohol to ketone and transformation of ester to Weinredtype amide. All analogs containing a acidic proton at the benzilicposition, can also be alkylated with a fluoride source such asN-fluorobenzenesulfonimide (Synlett, 187, (1991)) or alkyl halide suchas methyl iodide and a base such as potassium tert-butoxide to givealpha fluoro analogs such as I (R₆═F or Me).

Scheme 9:Preparation of Derivatives of Quinoline of Formula I

Alternatively, derivatives of formula I containing a masked carbonylfunction in the form of a cyanohydrin of type XLVIII can be treated withtetra-butyl-ammonium fluoride in a solvent such as THF to give theketone XLIX. Reduction of the carbonyl function with an hydride sourcesuch as sodium borohydride in a solvent such as methanol provides thesecondary alcohol L. Mitsunubo type displacement of the benzylic alcoholwith appropriate nucleophiles such as a substituted thiophenol will givethe corresponding thio ether LI. Further manipulation of ester functionto the tertiary alcohol and oxidation of sulfur to sulfone with anoxidizing agent such as oxone in a solvent such a mixture ofTHF/MeOH/H₂O gives LIII. 1,2-Diols like XLVI can be cyclized tocarbonate XLVII using, for example, carbonyl diimidazole and heating.

Scheme 10:Preparation of 4-Pyridinyl Derivatives of Quinoline of Formula I

Another synthetic approaches to quinoline of formula I is derived fromcustom made or commercial 3-bromobenzyl halides like LV. The latter canbe derived from appropriately substituted benzaldehyde by addition ofalkyl or arylmagnesium or lithium salts followed by conversion of thecorresponding alcohol to the halide by using thionyl chloride, forexample, in a solvent such as benzene. 4-Pyridinyl acetate or4-pyridinyl acetonitrile can be deprotonated using a base such as NaHMDSand then alkylated with the benzylic halide LV or benzyl halide derivedfrom quinoline VIII (Scheme 2). The derivatives of type LVII, with anester functional group, can be hydrolyzed and decarboxylated to LVIIIusing an aqueous base such as NaOH followed by an acidic work-up.Alternatively, treatment of LVII with a nucleophiles likemethylmagnesium bromide for example, can produce tertiary alcohol likeLIX. Other functional group manipulation from an ester was described inScheme 8. The pyridinyl can be oxidized to the pyridinyl N-oxide with anoxidizing agent such as MMPP in a solvent such a mixture of CH₂Cl₂/MeOHto gives LX or LXI.

Scheme 11:Preparation of Stilbene Derivatives of Quinoline of Formula I

Intermediate such as LXII-containing a double bond can serve as aprecursor to compound of formula I. Condensation of aldehydes VHI withsubstituted acetic acid or acetonitrile and a base such as piperidineand heating will provide LXII. Alternatively, phosphonium salts LXV witha base such as potassium tert-butoxide in a solvent such as THF canreact with aldehyde of formula VIII. Reduction of the olefin usingcatalyst such as palladium on carbon in a solvent such as THF/MeOH underhydrogen atmosphere or polymer supported phenylhydrazide in a solventsuch as toluene with heating will provide compound like LXIII.Cyclopropanation of the double bond using trimethyl-sulfoxonium iodideand a base such as NaH in a solvent such as DMSO will give derivativesof formula LXIV.

Preparation of Intermediates Preparation of Quinolines Quinoline 018-(3-Bromomethyl-phenyl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

Step 1: 8-Bromo-6-methanesulfonylmethyl-quinoline

To a solution of 6-bromomethyl-8-bromoquinoline (60 g, 200 mmol,described in International Patent Publication WO 94/22852) in DMF (500mL) was added sodium methanesulfinate (27.6 g, 270 mmol). After stirringovernight at 21° C., the mixture was quenched with H₂O (2L), stirred for1 h, isolated by filtration, and washed with Et₂O to yield the8-Bromo-6-methanesulfonylmethyl-quinoline as a white solid.

Step 2: 8-Bromo-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

To a solution of the 8-Bromo-6-methanesulfonylmethyl-quinoline from Step1 above (60 g, 200 mmol) in THF (2L) at 0° C. (internal), was addedpotassium t-butoxide (260 mL, 1M, THF) over 30 min. After 0.5 h at 0°C., MeI (20 mL, 320 mmol) was added and the resulting reaction mixturestirred at 0° C. for 2 h. More potassium t-butoxide (200 mL, 1M, THF)was then added over 30 min, followed by MeI (20 mL, 320 mmol), and themixture stirred at rt for 2 h. The mixture was neutralised withsaturated NH₄Cl solution and extracted with EtOAc. The organic extractswere washed (H₂O), (brine), dried (MgSO₄), filtered and concentrated.Stirring the solid in ether, followed by filtration gave the8-Bromo-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline as a pale yellowsolid.

Step 3:{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-methanol

A mixture of the 8-Bromo-6-(1-methanesulfonyl-1-methyl-ethyl)-quinolinefrom Step 2 above (26 g, 79 mmol), 3-(hydroxymethyl)phenyl-boronic acid(14 g, 92 mmol), sodium carbonate (120 mL, 2M, H₂O), PdCl₂(Ph₃P)₂ (2 g)in DME (300 mL) was heated at 90-100° C. for 8 h. The resulting reactionmixture was filtered on a large plug/column of silica gel and the elutedwith EtOAc. The organic extracts were concentrated and the resultingsuspension diluted with Et₂O and stirred vigorously for 3 h. The desired{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-methanolwas isolated as a white solid by filtration.

Step 4:8-(3-Bromomethyl-phenyl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

A suspension of the{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-methanolcompound from Step 3 above (30 g, 85 mmol) in AcOH (140 mL) and HBr (48mL, 48% aq) was stirred for 18 h at 80° C. The resulting mixture wascooled to 0° C. and poured into 2L of cold NaOH (0.3N). The pH of theresulting solution was adjusted to 5 and filtered. The resulting solidwas dissolved in EtOAc, washed with saturated NaHCO₃ solution, brine,dried (MgSO₄), filtered and concentrated. Stirring the solid inether/EtOAc, followed by filtration gave desired8-(3-Bromomethyl-phenyl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinolineas a pale brown solid.

Quinoline 02{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-methanolO-methanesulfonate

To a solution of the alcohol from Quinoline 01, Step 3 (5.15 g, 17 mmol)in CH₂Cl₂ (150 mL) at −78° C. was added Et₃N (3.6 mL, 26 mmol) andmethanesulfonyl chloride (1.6 mL, 21 mmol). After 0.5 h at −78° C., themixture was neutralized with saturated NH₄Cl solution, diluted withwater, and extracted with ether. The organic extracts were washed (H₂O,brine), dried (MgSO₄), filtered, and concentrated to yield the titlecompound as a white foam.

Quinoline 033-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-benzaldehyde

Following the procedures described in Quinoline 01, Steps 1-3, butsubstituting 3-formylphenyl-boronic acid for3-(hydroxymethyl)-phenyl-boronic acid in Step 3, the title compound wasobtained as pale yellow solid.

Quinoline 04 3-(6-Isopropyl-quinolin-8-yl)-benzaldehyde

A mixture of 8-bromo-6-isopropyl-quinoline (9.79 g, 39 mmol, describedin International Patent Publication WO 94/22852),3-(formyl)-phenyl-boronic acid (11.7 g, 78 mmol), sodium carbonate (78mL, 2M, H₂O), Pd(Ph₃P)₄ (2.7 g, 2.3 mmol) in DME (200 mL) was heated at70° C. for 18 h. The reaction mixture was cooled to 21° C. then dilutedwith water and ethyl acetate. The organic extracts were washed (H₂O,brine), dried (MgSO₄), filtered and concentrated. Purification by flashchromatography (eluting with hexane/ethyl acetate, 80:20) provided thetitle compound.

Quinoline 05 [3-(6-Isopropyl-quinolin-8-yl)-phenyl]-acetic acid methylester

Step 1: (3-Bromo-phenyl)-acetic acid methyl ester

To a solution of 3-bromophenylacetic acid (10 g, 46 mmol) in CH₂Cl₂ (20mL) was added CH₂N₂ (Et₂O) until yellow coloration persisted. Theresulting reaction mixture was quenched with AcOH, and diluted with aNaHCO₃ solution and ethyl acetate. The organic extracts were washed(H₂O, brine), dried (MgSO₄), filtered and concentrated to provided the(3-Bromo-phenyl)-acetic acid methyl ester compound.

Step 2: [3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-aceticacid methyl ester

A solution of (3-Bromo-phenyl)-acetic acid methyl ester from Step 1(10.9 mg, 48 mmol), diboron pinacol ester (14.5 g, 57 mmol), KOAc (16.33g, 166 mmol) and PdCl₂(dppf) (1.94 g, 2.38 mmol) in DMF (250 mL) washeated at 80° C. under N₂ for 3 h. The resulting reaction mixture wascooled to 21° C. and diluted with water and ethyl acetate. The organicextracts were washed (H₂O, brine), dried (MgSO₄), filtered andconcentrated. Purification by flash chromatography (eluting withhexane/ethyl acetate, 65:35) provided the[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acidmethyl ester compound.

Step 3: [3-(6-Isopropyl-quinolin-8-yl)-phenyl]-acetic acid methyl ester

A solution of[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acidmethyl ester from Step 2 (4 g, 14 mmol), 8-bromo-6-isopropylquinoline (3g, 12 mmol), Na₂CO₃ (2M, 18 mL, 36 mmol) and Pd(PPh₃)₄ (692 mg, 0.6mmol) in DMF (250 mL) was heated at 80° C. under N₂ for 18 h. Theresulting reaction mixture was cooled to 21° C. and diluted with waterand ethyl acetate. The organic extracts were washed (H₂O, brine), dried(MgSO₄), filtered and concentrated. Purification by flash chromatography(eluting with hexane/ethyl acetate, 80:20) provided the[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-acetic acid methyl estercompound.

Quinoline 06 8-(3-Bromomethyl-phenyl)-6-isopropyl-quinoline

Quinoline 06 was prepared according to the procedure described inQuinoline 01, Steps 3 and 4, but 6-isopropyl-8-bromo-quinoline was usedas the starting material. Flash chromatography (hexane/EtOAc) affordedthe title compound as a yellow solid.

Quinoline 07 [3-(6-Isopropyl-quinolin-8-yl)-phenyl]-acetonitrile

To a solution of Quinoline 06 (1.0 g, 2.94 mmol) in CH₃CN (15 mL) wasadded KCN (244 mg, 3.74 mmol) and 18-crown-6 (100 mg, 0.37 mmol). Theresulting reaction mixture was stirred 18 h at 80° C., then diluted witha sodium bicarbonate solution and ethyl acetate. The organic extractswere washed (H₂O, brine), dried (MgSO₄), filtered and concentrated.Purification by flash chromatography (eluting with hexane/ethyl acetate,75:25) provided the title compound.

Quinoline 08 2-(8-Bromo-quinolin-6-yl)-2-methyl-propionitrile

Step 1: (8-Bromo-quinolin-6-yl)-acetonitrile

DMP (10 mL) and H₂O (5 mL) were added to 6-bromomethyl-8-bromoquinoline(3 g) (described in International Patent Publication WO 94/22852) andpotassium cyanide (1.6 g). After heating at 100° C. for 1 hour, theresulting mixture was quenched with H₂O (100 mL) and extracted withEtOAc. The combined organic extracts were washed with water (3×), brine,dried over MgSO₄, filtered and concentrated. Flash chromatography(hexane:EtOAc, 3:1) yielded the (8-Bromo-quinolin-6-yl)-acetonitrilecompound as a white solid.

Step 2: 2-(8-Bromoquinolin-6-yl)-2-methyl-propionitrile

To a solution of (8-Bromo-quinolin-6-yl)-acetonitrile from Step 1 (3 g,12.1 mmol) in THF (100 mL) at −78° C., was added MeI (1.7 mL, 27 mmol)followed by potassium t-butoxide (27 mL, 27 mmol). After 2 h at −78° C.,the resulting mixture was warmed to 0° C., was poured in saturatedaqueous NH₄Cl, then extracted with EtOAc (2×). The combined organicextracts were washed with brine, dried over MgSO₄, filtered andconcentrated. Flash chromatography (hexane:EtOAc, 3:1) afforded the2-(8-Bromoquinolin-6-yl)-2-methyl-propionitrile as a white solid.

Quinoline 092-[8-(3-Bromomethyl-phenyl)-quinolin-6-yl]-2-methyl-propionitrile

Quinoline 09 was prepared according to the procedure described above inQuinoline 01, Steps 3 and 4 but used Quinoline 08 as the startingmaterial. Flash chromatography (hexane/EtOAc) afforded the titlecompound as a yellow solid.

Preparations of Esters Ester 01 (4-Methanesulfonyl-phenyl)-acetic acidmethyl ester

(4-Methanesulfonyl-phenyl)-acetic acid was treated with an etheralsolution of diazomethane until completion of esterification by TLC. Thesolvent was evaporated, the residue triturated in hexane/ether andfiltered to afford the title compound as a white solid.

Ester 02 Hydroxy-(4-methylsulfanyl-phenyl)-acetic acid ethyl ester

To a solution of ethyl α-oxo 4-methylthiophenylacetate (obtained fromthioanisole and ethyl oxalyl chloride using procedure described in J.Med. Chem., p.403(1981) (30 g, 134 mmol) in EtOH at −78° C., was addedNaBH₄ (2.5 g, 66 mmol) portionwise. After 40 min at −78° C., theresulting reaction mixture was quenched by slow addition of a saturatedammonium chloride solution, allowed to warm to 21° C., poured into water(0.5L) and stirred for 2 h. The suspension was filtered to provide thetitle compound as a white solid.

Ester 03 Fluoro-(4-methylsulfanyl-phenyl)-acetic acid ethyl ester

To a solution of Ester 02 (10.9 g, 48 mmol) in CH₂Cl₂ (300 mL) at −78°C. was added [bis(2-methoxyethyl)amino]sulfur trifluoride (10 mL, 54mmol) dropwise. The resulting reaction mixture was warmed slowly to 10°C., then poured into an ether/NaHCO₃ solution. The organic extracts werewashed (H₂O), (brine), dried (MgSO₄), filtered, and concentrated.Purification by flash chromatography (eluting with hexane/ethyl acetate,95:5) provided the title compound as an oil.

Ester 04 (4-Methylsulfanyl-phenyl)-acetic acid methyl ester

(4-Methylsulfanyl-phenyl)-acetic acid was treated with an etheralsolution of diazomethane until completion of esterification. The solventwas evaporated, the residue triturated in hexane/ether, and filtered toafford the title compound as a white solid.

Ester 05 N-Isopropyl-2-(4-methanesulfonyl-phenyl)-acetamide

To a solution of (4-methanesulfonyl-phenyl)-acetic acid (2.5 g, 11.7mmol) in CH₂Cl₂ (20 mL) was added EDCI (2.46 g, 12.9 mmol) followed bydiisopropyl amine (1.2 mL) and DMAP (140 mg, 1.2 mmol). After 18 h at21° C., the resulting reaction mixture was diluted with a saturatedammonium chloride solution and ethyl acetate. The organic extracts werewashed (H₂O, brine), dried (MgSO₄), filtered and concentrated.Purification by flash chromatography (eluting with hexane/ethylacetate/THF, 35:60:5) provided the title compound as a white solid.

Ester 06 5-(4-Methanesulfonyl-benzyl)-3-methyl-[1,2,4]oxadiazole

Ester 06 prepared according to the procedure described in Example 83 butusing (4-methanesulfonyl-phenyl)-acetic acid as the starting material.Flash chromatography (hexane/EtOAc) afforded the title compound as ayellow solid.

Preparation of Ketones Ketone 013-Hydroxy-3-methyl-1-(4-methylsulfanyl-phenyl)-butan-2-one

To a solution of sodium tert-butoxide (12 g, 125 mmol), XANTPHOS (2.05g, 3.5 mmol) and Pd₂(dba)₃ (1.35 g, 1.5 mmol) in THF (600 mL) was added4-bromothioanisole (20 g, 98 mmol) and 3-hydroxy-3-methyl-butan-2-one(12 g, 117 mmol). The resulting reaction mixture was heated to 75° C.for 2 h then cooled to r.t. and diluted with water. The organic extractswere washed (H₂O), (brine), dried (MgSO₄), filtered and concentrated.Purification by flash chromatography (eluting with hexane/ethyl acetate,85:15-80:20) provided the title compound as a pale brown solid.

Ketone 02 3-Hydroxy-1-(4-methanesulfonyl-phenyl)-3-methyl-butan-2-one

To a solution of Ketone 91 (10.7 g, 48 mmol) in THF/MeOH (2:1, 375 mL)was added OXONE® (60 g, 98 mmol) followed by water (slowly, 125 mL).After 2 h, the reaction mixture was diluted with ether and a saturatedNaHCO₃ solution. The organic extracts were washed (H₂O), (brine), dried(MgSO₄), filtered and concentrated. Purification by stirring vigorouslyin hexane/ether and isolation by filtration gave the desired product asa pale yellow solid (8.3 g).

Ketone 03 1-(4-Fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-ethanone

Step 1: 1-(4-Fluoro-phenyl)-2-(4-methylsulfanyl-phenyl)-ethanone

To a solution of sodium tert-butoxide (480 mg, 5 mmol), BINAP (racemic,112 mg, 0.18 mmol) and Pd₂(dba)₃ (68 mg, 0.075 mmol) in THF (10 mL) wasadded 4-bromo-thioanisole (914 mg, 4.5 mmol) and 4-fluoro-acetophenone(690 mg, 5 mmol). The resulting reaction mixture was heated to 80° C.for 3 h then cooled to 21° C. and diluted with water. The organicextracts were washed (H₂O), (brine), dried (MgSO₄), filtered andconcentrated. Purification by flash chromatography (eluting withhexane/ethyl acetate, 8:2) provided the1-(4-Fluoro-phenyl)-2-(4-methylsulfanyl-phenyl)-ethanone compound as asolid after precipitation in ether/ethyl acetate.

Step 2: 1-(4-Fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-ethanone

Following the procedures described in Ketone 02 but substituting1-(4-fluoro-phenyl)-2-(4-methylsulfanyl-phenyl)-ethanone for Ketone 01,the 1-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-ethanone compoundwas obtained as a white solid.

Ketone 04 2-(4-Methanesulfonyl-phenyl)-1-p-tolyl-ethanone

Following the procedures described in Ketone 03, but substituting4-methyl-acetophenone for 4-fluoro-acetophenone, the title compound wasobtained as a white solid.

Ketone 05 2-(4-Methanesulfonyl-phenyl)-1-pyridin-2-yl-ethanone

Following the procedures described in Ketone 03, but substituting2-acetylpyridine for 4-fluoroacetophenone, the title compound wasobtained as a beige solid.

Ketone 06 2-(4-Methanesulfonyl-phenyl)-1-pyridin-3-yl-ethanone

Following the procedures described in Ketone 03, but substituting3-acetyl-pyridine for 4-fluoro-acetophenone, the title compound wasobtained.

Ketone 07 1-(4-Methanesulfonyl-phenyl)-3,3-dimethyl-butan-2-one

Following the procedures described in Ketone 03, but substitutingpinacolone for 4-fluoroacetophenone, the title compound was obtained asa white solid.

Ketone 08 1-Cyclopropyl-2-(4-methanesulfonyl-phenyl)-ethanone

Following the procedures described in Ketone 01 and Ketone 02, butsubstituting 1-cyclopropyl-ethanone for 3-hydroxy-3-methyl-butan-2-one,the title compound was obtained.

Ketone 09 1-(4-Fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-propan-1-one

To a solution of Ketone 03 (240 mg, 0.822 mmol) in THF (8 mL) at −30° C.was added potassium tert-butoxide (1M, THF, 0.9 mL, 0.9 mmol) dropwise.After 20 min, iodomethane (0.076 mL, 1.22 mmol) was added and theresulting reaction mixture was stirred for 2 h at −20° C., and thendiluted with a saturated ammonium chloride solution and ethyl acetate.The organic extracts were washed (H₂O), (brine), dried (MgSO₄), filteredand concentrated. Purification by flash chromatography (eluting withtoluene/acetone, 95:5) provided the title compound.

Ketone 10 4-(4-Methanesulfonyl-phenyl)-2,2-dimethyl-pentan-3-one

Following the procedures described in Ketone 01, but substitutingpinacolone for 3-hydroxy-3-methyl-butan-2-one, followed by theprocedures described in Ketone 09 and finally using procedures describedin Ketone 02, the title compound was obtained.

Ketone 113-Hydroxy-1-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-3-methyl-butan-2-one

Step 1: 2-(4-Bromo-phenyl)-propan-2-ol

Following the procedures described in Example 24, but substituting ethyl4-bromobenzoate for Example 07, the 2-(4-bromo-phenyl)-propan-2-olcompound was obtained as a white solid.

Step 2:3-Hydroxy-1-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-3-methyl-butan-2-one

Following the procedures described in Ketone 01, but substituting2-(4-bromophenyl)-2-propanol for 4-bromothioanisole, the3-hydroxy-1-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-3-methyl-butan-2-onecompound was obtained as an oil.

Ketone 12 3-Ethyl-3-hydroxy-1-(4-methanesulfonyl-phenyl)-pentan-2-one

Step 1: 3-Ethyl-3-hydroxy-pentan-2-one

To a solution of ethyl vinylether (10 mL, 104 mmol) in THF (50 mL) at−78° C. was added tert-BuLi (1.7M, pentane, 45 mL, 76 mmol) dropwise.The mixture was stirred at −10° C. for 15 min then cooled to −78° C. and3-pentanone (5.0 g, 58 mmol, in 5 mL of THF) was added dropwise. Theresulting reaction mixture was allowed to warm slowly to 21° C., thendiluted with a saturated ammonium chloride solution and ethyl acetate.The organic extract was stirred with 6 mL of HCl 2% for 18 h then washed(H₂O, brine), dried (MgSO₄), filtered and concentrated. The residue waspurified by flash chromatography (eluting with hexane/ethyl acetate,95:5) to provide the 3-ethyl-3-hydroxy-pentan-2-one compound as an oil.

Step 2: 3-Ethyl-3-hydroxy-1-(4-methanesulfonyl-phenyl)-pentan-2-one

Following the procedures described in Ketone 01 then in Ketone 02, butsubstituting 3-ethyl-3-hydroxy-pentan-2-one for3-hydroxy-3-methyl-butan-2-one. Purification by flash chromatography(eluting with ethyl acetate/hexane, 3:2) afforded the3-ethyl-3-hydroxy-1-(4-methanesulfonyl-phenyl)-pentan-2-one compound asa white foam.

Preparation of Sulfones Sulfone 011-Methanesulfonyl-4-methanesulfonylmethyl-benzene

To a solution of 4-methanesulfonylbenzyl chloride (2 g, 10 mmol) in DMF(20 mL) at 21° C. was added sodium methanesulfinate (1.5 g, 15 mmol).After 18 h, the mixture is poured into cold water (100 mL), stirred for30 min then filtered off to afford the title compound as a white solid.

Sulfone 02 1-(Fluoro-methanesulfonyl-methyl)-4-methanesulfonyl-benzene

To a solution of Sulfone 01 (275 mg, 1.1 mmol) in DMF (6 mL) at 0° C.was added potassium tert-butoxide (1M THF, 1.5 mL, 1.5 mmol) followed,after 10 min, by N-fluorobenzenesulfonimide (419 mg, 1.3 mmol). Thereaction mixture was diluted with a saturated sodium bicarbonatesolution and ethyl acetate. The organic extracts were washed (H₂O),(brine), dried (MgSO₄), filtered and concentrated. Purification by flashchromatography (eluting with CH₂Cl₂/acetone, 97:3) provided the titlecompound.

Sulfone 03 1-Cyclopropanesulfonylmethyl-4-methanesulfonyl-benzene

Step 1: (4-Methylsulfanyl-phenyl)-methanethiol disulfide

A solution of sulfur (1 g, 29 mmol) in benzene (60 mL), PEG 400 (1 drop)and NaOH (5N, 46 mL, 232 mmol) was heated at 65° C. for 3 h.4-methylthiobenzyl chloride (4 g, 23 mmol) and a catalytic amount oftetrabutylammonium iodide was added and the mixture stirred at 65° C.for 2 h. The reaction was cooled at 21° C. and diluted with a saturatedammonium chloride solution and ethyl acetate. The organic extracts werewashed (H₂O), (brine), dried (MgSO₄), filtered and concentrated. Theresidue was stirred vigorously in ethanol/ether for 1 h then filtered toafford the (4-methylsulfanyl-phenyl)-methanethiol disulfide compound asa pale rose powder.

Step 2: 1-Cyclopropylsulfanylmethyl-4-methylsulfanyl-benzene

To a solution of (4-methylsulfanyl-phenyl)-methanethiol disulfide fromStep 1 in THF (50 mL) at 21° C. was added cyclopropylmagnesium bromide(excess) dropwise. The reaction mixture was stirred 18 h at 21° C., thendiluted with a saturated ammonium chloride solution and ethyl acetate.The organic extracts were washed (H₂O), (brine), dried (MgSO₄), filteredand concentrated. Purification by flash chromatography (eluting withhexane/ethyl acetate, 98:2) provided the1-cyclopropylsulfanylmethyl-4-methylsulfanyl-benzene compound as an oil.

Step 3: 1-Cyclopropanesulfonylmethyl-4-methanesulfonyl-benzene

Following the procedures described in Example 16, but substituting1-cyclopropylsulfanylmethyl-4-methylsulfanyl-benzene thioether from Step2 for Example 15 and purification by flash chromatography (eluting withhexane/ethyl acetate, 50:50 to 0:100) provided the1-cyclopropanesulfonylmethyl-4-methanesulfonyl-benzene compound as asolid.

Sulfone 04 1-Ethanesulfonylmethyl-4-methanesulfonyl-benzene

Step 1: 1-Ethylsulfanylmethyl-4-methanesulfonyl-benzene

To a solution of ethanethiol (0.3 mL, 4.9 mmol) and4-methanesulfonylbenzyl chloride (1 g, 4,9 mmol) in DMF (10 mL) at 21°C. was added cesium carbonate (0.8 g, 2.5 mmol). After 18 h, thereaction mixture was poured into water and then filtered off to providethe 1-ethylsulfanylmethyl-4-methanesulfonyl-benzene compound as a whitesolid.

Step 2: 1-Ethanesulfonylmethyl-4-methanesulfonyl-benzene

Following the procedures described in Example 16, but substituting the1-ethylsulfanylmethyl-4-methanesulfonyl-benzene thioether from Step 1for Example 15, the 1-ethanesulfonylmethyl-4-methanesulfonyl-benzenecompound was isolated as a white solid.

Sulfone 052-(4-Methanesulfonyl-phenylmethanesulfonyl)-1-methyl-1H-imidazole

Step 1: 2-(4-Methanesulfonyl-benzylsulfanyl)-1-methyl-1H-imidazole

To a solution of 2-mercapto-N-methylimidazole (570 mg, 4.9 mmol) and4-methanesulfonylbenzyl chloride (1 g, 4,9 mmol) in DMF (10 mL) at 21°C. was added cesium carbonate (0.8 g, 2.5 mmol). After 18 h, thereaction mixture was diluted with water and ethyl acetate. The organicextracts were washed (H₂O), (brine), dried (MgSO₄), filtered andconcentrated to provide the2-(4-methanesulfonyl-benzylsulfanyl)-1-methyl-1H-imidazole compound as awhite solid.

Step 2:2-(4-Methanesulfonyl-phenylmethanesulfonyl)-1-methyl-1H-imidazole

Following the procedures described in Example 16, but substituting the2-(4-methanesulfonyl-benzylsulfanyl)-1-methyl-1H-imidazole thioetherfrom Step 1 for Example 15, the2-(4-methanesulfonyl-phenylmethanesulfonyl)-1-methyl-1H-imidazolecompound was isolated as a white solid.

Sulfone 06 2-(4-Methanesulfonyl-phenylmethanesulfonyl)-thiazole

Following the procedures described in Sulfone 04, but substituting2-mercaptothiazole for ethanethiol, the title compound was obtained as awhite solid.

Sulfone 07 2-(4-Methanesulfonylmethyl-phenyl)-propan-2-ol

Step 1: 4-Methanesulfonylmethyl-benzoic acid methyl ester

Following the procedures described in Sulfone 01, but substituting4-carboxymethylbenzyl chloride for 4-methanesulfonylbenzyl chloride, the4-methanesulfonylmethyl-benzoic acid methyl ester compound was obtainedas a white solid.

Step 2: 2-(4-Methanesulfonylmethyl-phenyl)-propan-2-ol

Following the procedures described in Example 29, but substituting the4-methanesulfonylmethyl-benzoic acid methyl ester from Step 1 forExample 27, the 2-(4-methanesulfonylmethyl-phenyl)-propan-2-ol compoundwas obtained as a white solid.

Sulfone 08 C-(4-Methanesulfonyl-phenyl)-N,N-dimethyl-methanesulfonamide

Step 1: (4-Methanesulfonyl-phenyl)-methanethiol

To a solution of potassium acetate (5.86 g, 51 mmol) in THF/DMF (3:1,400 mL) was added 4-methanesulfonylbenzyl chloride (10 g, 49 mmol).After 3 h at 21° C., the resulting reaction mixture was quenched withLiOH (1M) and stirred again for 2 h. The mixture was diluted with HCl10% solution and ethyl acetate. The organic extracts were washed (H₂O),(brine), dried (MgSO₄), filtered and concentrated. Purification by flashchromatography (eluting with CH₂Cl₂) provided the(4-methanesulfonyl-phenyl)-methanethiol compound.

Step 2: (4-Methanesulfonyl-phenyl)-methanesulfonyl chloride

To a solution of the (4-methanesulfonyl-phenyl)-methanethiol from Step 1(7.3 g, 36 mmol) in AcOH (75 mL) was added water (25 mL). Then, chlorinewas bubbled in the resulting mixture for 2 min. The mixture was dilutedwith water and filtered to provide the(4-methanesulfonyl-phenyl)-methanesulfonyl chloride.

Step 3: C-(4-Methanesulfonyl-phenyl)-N,N-dimethyl-methanesulfonamide

To a solution of (4-methanesulfonyl-phenyl)-methanesulfonyl chloridefrom Step 2 (1.0 g, 3.7 mmol) in CH₂Cl₂ (40 mL) was added dimethylamine(0.42 g, 9.3 mmol) dropwise. After 18 h, the resulting reaction mixturewas diluted with a saturated ammonium chloride solution and ethylacetate. The organic extracts were washed (HCl 10%, NaHCO₃, brine),dried (MgSO₄), filtered, and concentrated to provided theC-(4-methanesulfonyl-phenyl)-N,N-dimethyl-methanesulfonamide compound.

Sulfone 091-(4-Cyclopropanesulfonyl-phenyl)-3-hydroxy-3-methyl-butan-2-one

Step 1: 4-bromobenzene disulfide

To a solution of 4-bromothiophenol (16 g, 85 mmol) in CH₂Cl₂ (85 mL) wasadded iodine (10.7 g, 42 mmol, in CH₂Cl₂) and triethylamine (11.8 mL, 85mmol). After 3 h the resulting reaction mixture was diluted with asodium bisulfite solution and ethyl acetate. The organic extracts werewashed (1N NaOH, brine), dried (MgSO₄), filtered and concentrated. Theresulting residue was stirred vigorously in hexane/ether for 1 h thenfiltered to afford the 4-bromobenzene disulfide compound as a whitepowder.

Step 2: 1-Bromo-4-cyclopropylsulfanyl-benzene

Following the procedures described in Sulfone 03, Step 2 andpurification by flash chromatography (eluting with hexane) provided the1-bromo-4-cyclopropylsulfanyl-benzene compound.

Step 3: 1-(4-Cyclopropylsulfanyl-phenyl)-3-hydroxy-3-methyl-butan-2-one

Following the procedures described in Ketone 01, but substituting the1-bromo-4-cyclopropylsulfanyl-benzene from Step 2 for4-bromothioanisole, the1-(4-cyclopropylsulfanyl-phenyl)-3-hydroxy-3-methyl-butan-2-one compoundwas obtained.

Step 4: 1-(4-Cyclopropanesulfonyl-phenyl)-3-hydroxy-3-methyl-butan-2-one

Following the procedures described in Ketone 02, but substituting the1-(4-cyclopropylsulfanyl-phenyl)-3-hydroxy-3-methyl-butan-2-one fromStep 3 for Ketone 01, the1-(4-cyclopropanesulfonyl-phenyl)-3-hydroxy-3-methyl-butan-2-onecompound was obtained.

Preparation of Phosphonates Phosphonate 01(4-Methanesulfonyl-benzyl)-phosphonic acid dimethyl ester

Step 1: (4-Methylsulfanyl-benzyl)-phosphonic acid dimethyl ester

To trimethylphosphite (8.6 g, 70 mmol) at 140° C. was added4-methylthiobenzyl chloride (10 g, 58 mmol). The resulting mixture wasstirred at 140° C. for 18 h, cooled at 21° C. then diluted with HCl 10%and ethyl acetate. The organic extracts were washed (H₂O), (brine),dried (MgSO₄), filtered, and concentrated. Purification by flashchromatography (eluting with ethyl acetate) provided the(4-methylsulfanyl-benzyl)-phosphonic acid dimethyl ester compound.

Step 2: (4-Methanesulfonyl-benzyl)-phosphonic acid dimethyl ester

Following the procedures described in Example 16, but substituting(4-methylsulfanyl-benzyl)-phosphonic acid dimethyl ester from Step 1 forExample 15, the (4-methanesulfonyl-benzyl)-phosphonic acid dimethylester compound was isolated.

Phosphonate 02 [Fluoro-(4-methanesulfonyl-phenyl)-methyl]-phosphonicacid dimethyl ester

Following the procedures described in Example 37, but substitutingPhosphonate 01 for Example 1, using THF as solvent, and purification byflash chromatography (eluting with toluene/acetone, 1:1) afforded thetitle compound.

Phosphonate 032-(4-Methanesulfonyl-benzyl)-5,5-dimethyl-[1,3,2]dioxaphosphinane2-oxide

Step 1: (4-Methanesulfonyl-benzyl)-phosphonic acid

To a solution of Phosphonate 01 (5.74 g, 20.6 mmol) in CHCl₃ (50 mL) wasadded TMSBr (27 mL, 206 mmol) dropwise. The resulting reaction mixturewas stirred 18 h at 21° C., concentrated under vacuum, and diluted withCHCl₃ and EtOH. After 2 h of stirring at 21° C., the mixture wasconcentrated again under vacuum. The resulting residue was crystallizedfrom CH₂Cl₂/hexane as a white solid.

Step 2: (4-Methanesulfonyl-benzyl)-phosphonoyl chloride

To a solution of (4-methanesulfonyl-benzyl)-phosphonic acid from Step 1(5.3 g, 21 mmol) in CH₂Cl₂ (200 mL) was added oxalyl chloride (4 mL, 45mmol) dropwise and a few drops of DMF. After 5 days at 21° C., thesolvent was evaporated and the residue was used as such in the nextstep.

Step 3:2-(4-Methanesulfonyl-benzyl)-5,5-dimethyl-[1,3,2]dioxaphosphinane2-oxide

To a solution of (4-Methanesulfonyl-benzyl)-phosphonoyl chloride fromStep 2 (100 mg, 0.35 mmol) in CH₂Cl₂ (5 mL) was added triethylamine (0.1mL, 0.7 mmol) and 2,2-dimethyl-1,3-propanediol (48 mg, 0.47 mmol). Theresulting reaction mixture was stirred 48 h at 21° C., then diluted withwater and ethyl acetate. The organic extracts were washed (H₂O),(brine), dried (MgSO₄), filtered and concentrated. Purification bycrystallization from CH₂C₂/hexane provided the2-(4-methanesulfonyl-benzyl)-5,5-dimethyl-[1,3,2]dioxaphosphinane2-oxide compound as a white solid.

Phosphonate 04 (4-Methanesulfonyl-benzyl)-phosphonic acidbis-(2,2,2-trifluoro-ethyl)ester

Following the procedures described in Phosphonate 03, but substituting2,2,2-trifluoroethanol for 2,2-dimethyl-1,3-propanediol, the titlecompound was obtained.

EXAMPLE 14-Hydroxy-1-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-4-methyl-pentan-3-one

To a solution of Ketone 02 in THF/DMF (4:1, 0.08M) at 0° C. was addedpotassium tert-butoxide (1M, THF, 1.0 eq) dropwise followed after 10 minby Quinoline 01 (1.0 eq) dissolved in DMF (2M). The resulting reactionmixture was stirred at 21° C. for 3 h and diluted with a saturatedammonium acetate solution and ethyl acetate. The organic extracts werewashed (H₂O), (brine), dried (MgSO₄), filtered, and concentrated.Purification by flash chromatography (eluting with ethylacetate/dichloromethane, 60:40) provided the title compound as a whitefoam. The enantiomers can be separated on a chiral column (ChiralPaK AD,hexane/EtOH, 65:35, retention time 12.26 and 13.36 min) to give Example1A (first to elute, [α]_(D) 77.3 c=0.94 CH₂Cl₂) and Example 1B.

¹H NMR (400 MHz, acetone-d6): δ 8.93 (dd, 1H), 8.45 (dd, 1H), 8.26 (d,1H), 8.05 (d, 1H), 7.86 (d, 2H), 7.68 (d, 2H), 7.57 (m, 2H), 7.50 (d,1H), 7.35 (t, 1H), 7.21 (d, 1H), 5.18 (dd, 1H), 4.46 (s, OH), 3.45 (dd,1H), 3.08 (dd, 1H), 3.05 (s, 3H), 2.7 (s, 3H), 1.98 (s, 6H), 1.1 (s,3H), 1.05 (s, 3H).

EXAMPLE 21-(4-Fluoro-phenyl)-3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-propan-1-one

Following the procedures described in Example 1, but substituting Ketone03 for Ketone 02, the title compound was obtained as a white solid.

¹H NMR (400 MHz, acetone-d₆): δ 8.88 (dd, 1H), 8.68 (dd, 1H), 8.43 (dd,1H), 8.25 (d, 1H), 8.19-8.15 (m, 2H), 8.03 (d, 1H), 7.86 (d, 2H), 7.71(d, 2H), 7.64 (s, 1H), 7.55 (dd, 1H), 7.50 (app d, 1H), 7.30 (t, 1H),7.24 (app d, 1H), 7.19 (t, 2H), 5.47 (t, 1H), 3.22 (dd, 1H), 3.01 (s,3H), 2.71 (s, 3H), 1.97 (s, 6H).

EXAMPLE 33-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-1-p-tolyl-propan-1-one

Following the procedures described in Example 1, but substituting Ketone04 for Ketone 02, the title compound was obtained.

¹H NMR (400 MHz, acetone-d₆): δ 8.88 (dd, 1H), 8.43 (dd, 1H), 8.24 (d,1H), 8.02 (d, 1H), 7.98 (d, 2H), 7.85 (d, 2H), 7.71 (d, 2H), 7.64 (s,1H), 7.55 (dd, 1H), 7.50 (app d, 1H), 7.30 (t, 1H), 7.25 (app d, 3H),5.45 (t, 1H), 3.68 (dd, 1H), 3.20 (dd, 1H), 3.01 (s, 3H), 2.70 (s, 3H),2.32 (s, 3H), 1.97 (s, 6H).

EXAMPLE 43-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-1-pyridin-2-yl-propan-1-one

Following the procedures described in Example 1, but substituting Ketone05 for Ketone 02, the title compound was obtained.

¹H NMR (400 MHz, acetone-d₆): δ 8.86 (dd, 1H), 8.69 (d, 1H), 8.42 (dd,1H), 8.24 (d, 1H), 8.02-8.01 (m, 2H), 7.94 (td, 1H), 7.83 (d, 2H), 7.72(d, 2H), 7.64 (s, 1H), 7.59-7.56 (m, 1H), 7.54 (dd, 1H), 7.50 (app d,1H), 7.33-7.26 (m, 2H), 6.06 (t, 1H), 3.70 (dd, 1H), 3.27 (dd, 1H), 3.01(s, 3H), 2.70 (s, 3H), 1.97 (s, 6H).

EXAMPLE 53-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-1-pyridin-3-yl-propan-1-one

Following the procedures described in Example 1, but substituting Ketone06 for Ketone 02, the title compound was obtained.

¹H NMR (400 MHz, acetone-d₆): δ 9.22 (d, 1H), 8.89 (dd, 1H), 8.69 (dd,1H), 8.43 (dd, 1H), 8.36 (dt, 1H), 8.25 (d, 1H), 8.03 (d, 1H), 7.87 (d,2H), 7.73 (d, 2H), 7.65 (s, 1H), 7.55 (dd, 1H), 7.49 (app d, 1H), 7.45(dd, 1H), 7.31 (t, 1H), 7.25 (app d, 1H), 5.52 (t, 1H), 3.70 (dd, 1H),3.25 (dd, 1H), 3.01 (s, 3H), 2.71 (s, 3H), 1.97 (s, 6H).

EXAMPLE 61-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-4,4-dimethyl-pentan-3-one

Following the procedures described in Example 1, but substituting Ketone07 for Ketone 02, the title compound was obtained as white foam.

¹H NMR (400 MHz, acetone-d6): δ 8.93 (dd, 1H), 8.44 (dd, 1H), 8.25 (d,1H), 8.04 (d, 1H), 7.87 (dd, 2H), 7.56 (m, 2H), 7.50 (d, 1H), 7.33 (t,1H), 7.21 (d, 1H), 7.2 (dd, 2H), 4.89 (dd, 1H), 3.39 (dd, 1H), 3.06 (s,3H), 3.04 (dd, 1H), 2.71 (s, 3H), 1.98 (s, 6H), 0.95 (s, 9H). 99254-47.

EXAMPLE 73-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-propionicacid methyl ester

To a solution of Ester 01 (1.26 g, 5.5 mmol) in THF (80 mL) at −78° C.was added LiHMDS (1M, THF, 6.6 mL, 6.6 mmol) dropwise followed, after 30min, Quinoline 01 (2.1 g, 5.0 mmol) dissolved in DMF (8 mL). Thereaction mixture was stirred at −78° C. for 2 h and diluted with asaturated ammonium chloride solution and ethyl acetate. The organicextracts were washed (H₂O), (brine), dried (MgSO₄), filtered andconcentrated. Purification by flash chromatography (eluting withhexane/ethyl acetate, 40:60) provided the title compound as a whitefoam.

¹H NMR (400 MHz, acetone-d6): δ 8.92 (dd, 1H), 8.43 (dd, 1H), 8.25 (d,1H), 8.06 (d, 1H), 7.99 (d, 2H), 7.9 (d, 2H), 7.57 (m, 3H), 7.34 (t,1H), 7.24 (d, 1H), 4.24 (t, 1H), 3.62 (s, 3H), 3.54 (dd, 1H), 3.29 (dd,1H), 3.07 (s, 3H), 1.99 (s, 6H).

EXAMPLE 83-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-propionicacid

To a solution of Example 7 (130 mg, 0.23 mmol) in THF/MeOH/H₂O (2:2:1, 5mL) was added LiOH (2M, 0.35 mL, 0.69 mmol). The resulting mixture wasstirred at 21° C. 18 h, acidified with HCl 10% and diluted with ethylacetate. The organic extracts were washed (H₂O), (brine), dried (MgSO₄),filtered and concentrated. The title compound was obtained as a whitepowder after sonication in ether/hexane and filtration.

¹H NMR (400 MHz, acetone-d6): δ 8.92 (dd, 1H), 8.43 (dd, 1H), 8.25 (d,1H), 8.06 (d, 1H), 7.9 (d, 2H), 7.70 (d, 2H), 7.62 (s, 1H), 7.54 (m,2H), 7.34 (t, 1H), 7.26 (d, 1H), 4.22 (dd, 1H), 3.55 (dd, 1H), 3.39 (dd,1H), 3.07 (s, 3H), 2.71 (s, 3H), 1.98 (s, 6H).

EXAMPLE 91-Cyclopropyl-3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-propan-1-one

Step 1:3-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-N-methoxy-N-methyl-propionamide

To a solution of N,O-dimethylhydroxylamine (free base, 260 mg, 4.2 mmol)in THF at −78° C. was added MeMgBr (3M, ether, 1.4 mL, 4.2 mmol)dropwise (internal temperature <−65° C.) followed, after 30 min, byExample 7 (600 mg, 1.06 mmol, in THF). The resulting mixture was warmedslowly to 21° C., diluted with ethyl acetate and saturated ammoniumchloride solution. The organic extracts were washed (H₂O), (brine),dried (MgSO₄), filtered, and concentrated. Purification by flashchromatography (eluting with hexane/ethyl acetate, 1:4 to 1:9) providedthe3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-N-methoxy-N-methyl-propionamidecompound as a white foam.

Step 2:1-Cyclopropyl-3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-propan-1-one

Anhydrous CeCl₃ (266 mg, 1.26 mmol) was heated 2 h at 130° C. under highvacuum, refluxed in THF (10 mL) for 1 h then cooled to 0° C. To theresulting white suspension at 0° C. was added freshly preparedcyclopropylmagnesium bromide (0.6M, THF, 2.11 mL, 1.25 mmol) and theresulting mixture stirred at 0° C. for 1 h then cooled to −78° C. The3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-N-methoxy-N-methyl-propionamidefrom Step 1 (in THF, 150 mg, 0.25 mmol) was added and the mixture warmedto 0° C. for 1 h, diluted with ethyl acetate and saturated ammoniumchloride solution. The organic extracts were washed (H₂O), (brine),dried (MgSO₄), filtered and concentrated. Purification by flashchromatography (eluting with hexane/ethyl acetate, 1:4) provided the1-cyclopropyl-3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-propan-1-onecompound as a white foam.

¹H NMR (400 MHz, acetone-d6): δ 8.93 (dd, 6H), 8.42 (dd, 1H), 8.25 (d,1H), 8.06 (d, 1H), 7.95 (d, 2H), 7.63 (d, 2H), 7.54 (m, 3H), 7.31 (t,1H), 7.20 (d, 1H), 4.61 (t, 1H), 3.56 (dd, 1H), 3.09 (dd, 1H), 3.05 (s,3H), 2.71 (s, 3H), 2.06 (m, 1H), 1.98 (s, 6H), 0.9-0.7 (m, 4H).

An alternate synthesis of Example 9 is by following the proceduresdescribed above in Example 1, but substituting Ketone 08 for Ketone 02.

EXAMPLE 105-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}4-(4-methanesulfonyl-phenyl)-2,3-dimethyl-pentane-2,3-diol

Using Example 01 as the starting material and following the proceduresdescribed above in Example 9, Step 2, and substituting methylmagnesiumbromide for cyclopropyl magnesium bromide, the title compound wasobtained as a white solid (one pair of enantiomer).

¹H NMR (400 MHz, acetone-d6): δ 8.89 (dd, 1H), 8.38 (dd, 1H), 8.20 (d,1H), 7.95 (d, 1H), 7.71 (d, 2H), 7.61 (d, 2H), 7.50 (dd, 1H), 7.47 (s,1H), 7.39 (d, 1H), 7.16 (t, 1H), 7.08 (d, 1H), 3.74 (m, 2H), 3.63 (s,1H), 3.29 (s, 1H), 3.19 (m, 1H), 2.93 (s, 3H), 2.70 (s, 3H), 1.95 (s,6H), 1.41 (s, 6H), 1.32 (s, 3H).

EXAMPLE 111-Cyclopropyl-2-fluoro-3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-propan-1-one

To a solution of Example 9 (1.5 g, 2.62 mmol) in THF/DMF (3:1, 13 mL) at−78° C. was added potassium tert-butoxide (1M THF, 2.9 mL, 2.9 mmol),followed by N-fluorobenzenesulfonimide (1.63 g, 5.2 mmol). The resultingreaction mixture was stirred 2 h at −78° C., then quenched with AcOH (2drops) and diluted with a saturated ammonium chloride solution and ethylacetate. The organic extracts were washed (H₂O), (brine), dried (MgSO₄),filtered and concentrated. Purification by flash chromatography (elutingwith toluene/acetone, 80:20) provided the title compound.

¹H NMR (400 MH, acetone-d6): δ 8.90 (dd, 1H), 8.40 (dd, 1H), 8.24 (d,1H), 8.05 (d, 1H), 7.97 (d, 2H), 7.71 (d, 2H), 7.59 (d, 1H), 7.55 (s,1H), 7.53 (dd, 1H), 7.34 (t, 1H), 7.14 (d, 1H), 3.78 (dd, 1H), 3.52 (dd,1H), 3.09 (s, 3H), 2.70 (s, 3H), 2.49-2.41 (m, 1H), 1.98 (s, 6H),0.91-0.85 (m, 4H).

EXAMPLE 122-Cyclopropyl-3-fluoro-4-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-3-(4-methanesulfonyl-phenyl)-butan-2-ol

Using Example 11 as starting material and following the proceduresdescribed below in Example 29, the title compound was obtained as awhite solid (9:1 mixture of diastereoisomers). The enantiomers can beseparated on a chiral column (ChiralPaK AD, hexane/EtOH, 1;1, retentiontime 21 and 29 min) to give Example 12A and Example 12B.

¹H NMR (400 MHz, acetone-d6): (major isomer) δ 8.88 (dd, 1H), 8.38 (dd,1H), 8.20 (d, 1H), 7.91 (d, 1H), 7.83 (d, 2H), 7.78 (d, 2H), 7.51 (dd,1H), 7.45 (s, 1H), 7.44 (d, 1H), 7.18 (t, 1H), 7.14 (d, 1H), 4.11 (s,OH), 3.83 (s, 1H), 3.77 (dd, 1H), 2.97 (s, 3H), 2.70 (s, 3H), 1.97 (s,3H), 1.96 (s, 3H), 1.34 (d, 3H), 0.96-0.92 (m, 1H), 0.34-0.22 (m, 3H),0.14-0.10 (m, 1H). LRMS (CI) 610 (M+H)⁺.

The other pair of enantiomers can be obtained using Example 14 as thestarting material and following procedures described in Example 11followed with the procedures described above in Example 9, Step 2 (85:15mixture of diastereoisomers).

¹H NMR (400 MHz, acetone-d6): δ 8.88 (dd, 1H), 8.40 (dd, 1H), 8.21 (d,1H), 7.91 (d, 1H), 7.79 (m, 4H), 7.52 (dd, 1H), 7.43 (m, 2H), 7.15 (m,2H), 4.1-3.6 (m, 3H), 3.89 (s, 3H), 2.70 (s, 3H), 1.97 (d, 6H), 1.29 (m,1H), 1.09 (d, 3H), 0.81 (m, 1H), 0.56 (m, 1H), 0.38 (m, 2H).

EXAMPLE 133-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-1-phenyl-propan-1-one

Step 1:3-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methylsulfanyl-phenyl)-propionicacid methyl ester

To a solution of Ester 04 (4.0 g, 20 mmol) in THF (5 mL) at −78° C. wasadded KHMDS (0.5M, Tol, 41 mL, 20.5 mmol) dropwise. The resultingreaction mixture was stirred 0.5 h at −78° C. then cannulated intoQuinoline 02 (2.95 g, 6.8 mmol) in THF (50 mL) at 21° C. After 15 min,the mixture was diluted with a saturated ammonium chloride solution andethyl acetate. The organic extracts were washed (H₂O), (brine), dried(MgSO₄), filtered and concentrated. Purification by flash chromatography(eluting with hexane/ethyl acetate, 50:50) provided the3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methylsulfanyl-phenyl)-propionicacid methyl ester compound as a white foam.

Step 2:3-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methylsulfanyl-phenyl)-propionaldehyde

To a solution of3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methylsulfanyl-phenyl)-propionicacid methyl ester from Step 1 (1.48 g, 7.5 mmol) in CH₂Cl₂ (80 mL) at−78° C. was added dibal-H (1.6 mL, 7.8 mmol). The resulting reactionmixture was stirred 1 h at −78° C., then quenched with sodium potassiumtartrate solution and stirred at 21° C. for 3 h. The organic extractswere washed (H₂O), (brine), dried (MgSO₄), filtered and concentrated toprovided the3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methylsulfanyl-phenyl)-propionaldehydecompound as a white foam.

Step 3:3-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methylsulfanyl-phenyl)-1-phenyl-propan-1-ol

To a solution of3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methylsulfanyl-phenyl)-propionaldehydefrom Step 2 (150 mg, 0.3 mmol) in CH₂Cl₂ (6 mL) at 21° C. was addedphenylmagnesium chloride (2M, TBF, 0.45 mL, 0.9 mmol) dropwise. Theresulting reaction mixture was stirred 0.5 h at 21° C. then diluted witha saturated ammonium chloride solution and ethyl acetate. The organicextracts were washed (H₂O), (brine), dried (MgSO₄), filtered andconcentrated. The crude oil was used as such in the next step.

Step 4:3-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methylsulfanyl-phenyl)-1-phenyl-propan-1-one

To a solution of the crude oil from Step 3 in CH₂Cl₂ (5 mL) at 21° C.was added Dess-Martin periodinane (255 mg, 0.6 mmol) portionwise. Theresulting reaction mixture was stirred 2 h at 21° C., then diluted witha sodium bicarbonate solution and ethyl acetate. The organic extractswere washed (H₂O), (brine), dried (MgSO₄), filtered and concentrated.Purification by flash chromatography (eluting with hexane/ethyl acetate,50:50) provided the3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methylsulfanyl-phenyl)-1-phenyl-propan-1-onecompound as a white foam.

Step 5:3-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-1-phenyl-propan-1-one

To a solution of3-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl)-phenyl)-2-(4-methylsulfanyl-phenyl)-1-phenyl-propan-1-onefrom Step 4 (55 mg, 0.095 mmol) in THF/MeOH/H₂O (2:1:1, 5 mL) at 21° C.was added OXONE® (0.1 g, 0.16 mmol). The resulting reaction mixture wasstirred 2 h at 21° C., then diluted with a sodium bicarbonate solutionand ethyl acetate. The organic extracts were washed (H₂O), (brine),dried (MgSO₄), filtered and concentrated. The residue was stirredvigorously in hexane/ether for 1 h then filtered to afford the3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-1-phenyl-propan-1-onecompound as a white powder.

¹H NMR (400 MHz, acetone-d6): δ 8.87 (dd, 1H), 8.42 (dd, 1H), 8.24 (d,1H), 8.08 (d, 2H), 8.03 (d, 1H), 7.85 (d, 2H), 7.71 (d, 2H), 7.65 (s,1H), 7.56-7.42 (m, 5H), 7.28 (m, 2H), 5.5 (t, 1H), 3.69 (dd, 1H), 3.23(dd, 1H), 3.00 (s, 3H), 2.70 (s, 3H), 1.97 (s, 6H). 99020-173

EXAMPLE 14 4-{3-[6-(1-Methanesulfonyl-1methyl-ethyl)-quinolin-8-yl]-phenyl}-3-(4-methanesulfonyl-phenyl)-butan-2-one

Following the procedures described above in Example 13, but substitutingmethylmagnesiumbromide for phenylmagnesium bromide in Step 3, the titlecompound was obtained as a white solid.

¹H NMR (400 MHz, acetone-d6): δ 8.92 (dd, 1H), 8.43 (dd, 1H), 8.25 (d,1H), 8.03 (d, 1H), 7.95 (d, 2H), 7.62 (d, 2H), 7.60-7.52 (m, 3H), 7.31(t, 1H), 7.18 (d, 1H), 4.50 (t, 1H), 3.52 (dd, 1H), 3.10 (dd, 1H), 3.05(s, 3H), 2.83 (s, 3H), 2.11 (s, 3H), 1.98 (s, 6H).

EXAMPLE 153-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methylsulfanyl-phenyl)-propan-1-ol

To a solution of the ester from Step 1, Example 13 (1.0 g, 5 mmol) inCH₂Cl₂ (25 mL) at −78° C. was added dibal-H (20.1 mL, 12 mmol). Theresulting reaction mixture was warmed slowly to 21° C., then quenchedwith sodium potassium tartrate solution and stirred at 21° C. for 3 h.The reaction mixture was diluted with ethyl acetate. The organicextracts were washed (H₂O), (brine), dried (MgSO₄), filtered andconcentrated. Purification by flash chromatography (eluting withhexane/ethyl acetate, 50:50) provided the title compound as a whitefoam.

¹H NMR (400 MHz, acetone-d6): δ 8.91 (dd, 1H), 8.43 (dd, 1H), 8.24 (d,1H), 8.01 (d, 1H), 7.56 (dd, 1H), 7.51 (m, 2H), 7.29 (t, 1H), 7.24-7.14(m, 6H), 3.75 (d, 2H), 3.27 (dd, 1H), 3.14 (m, 1H), 2.96 (dd, 1H), 2.70(s, 3H), 2.42 (s, 3H), 1.98 (s, 6H).

EXAMPLE 163-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-propan-1-ol

To a solution of Example 15 (350 mg, 0.69 mmol) in THF/MeOH/H₂O (2:1:1,15 mL) at 21° C. was added OXONE® (1.1 g, 1.8 mmol). The resultingreaction mixture was stirred 2 h at 21° C. then diluted with a sodiumbicarbonate solution and ethyl acetate. The organic extracts were washed(H₂O), (brine), dried (MgSO₄), filtered and concentrated to afford thetitle compound as a pale yellow foam.

¹H NMR (400 MHz, acetone-d6): δ 8.91 (dd, 1H), 8.42 (dd, 1H), 8.24 (d,1H), 8.04 (d, 1H), 7.82 (d, 2H), 7.55 (m, 5H), 7.31 (t, 1H), 7.20 (d,1H), 3.83 (d, 2H), 3.34 (m, 2H), 3.05 (m, 1H), 3.03 (s, 3H), 2.70 (s,3H), 1.98 (s, 6H).

EXAMPLE 172-Hydroxy-3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-propionicacid ethyl ester

Step 1:2-Hydroxy-3-{3-(6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methylsulfanyl-phenyl)-propionicacid ethyl ester

To a solution of Ester 02 (220 mg, 0.97 mmol) in THF (6 mL) at −78° C.was added potassium tert-butoxide (1M, THF, 20.1 mL, 2.1 mmol) dropwise.The resulting reaction mixture was warmed to −40° C. for 20 min, thenQuinoline 01 (0.25M, THF, 3 mL) was added. The reaction mixture waswarmed from 40° C. to −20° C. over a 2 h period, then quenched with asaturated ammonium chloride solution and ethyl acetate. The organicextracts were washed (H₂O), (brine), dried (MgSO₄), filtered andconcentrated. Purification by flash chromatography (eluting withhexane/ethyl acetate, 50:50) provided the2-hydroxy-3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)quinolin-8-yl]-phenyl}-2-(4-methylsulfanyl-phenyl)-propionicacid ethyl ester compound as a white foam.

Step 2:2-Hydroxy-3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-propionicacid ethyl ester

Using the2-hydroxy-3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methylsulfanyl-phenyl)-propionicacid ethyl ester from Step 1 and following the procedures described inExample 16, and purification by flash chromatography (eluting withhexane/ethyl acetate, 1:4) provided the2-hydroxy-3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-propionicacid ethyl ester compound as a white foam.

¹H NMR (400 MHz, acetone-d6): δ 8.91 (dd, 1H), 8.42 (dd, 1H), 8.25 (d,1H), 8.07 (d, 1H), 8.02 (d, 2H), 7.93 (d, 2H), 7.65 (s, 1H), 7.56 (m,2H), 7.33 (m, 2H), 5.07 (s, OH), 4.17 (m, 2H), 3.71 (d, 1H), 3.33 (d,1H), 3.07 (s, 3H), 2.71 (s, 3H), 1.98 (s, 6H), 1.17 (m, 3H).

EXAMPLE 182-(4-Fluoro-phenyl)-4-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-3-(4-methanesulfonyl-phenyl)-butan-2-ol

To a solution of Example 02 (101 mg, 0.16 mmol) in THF (2 mL) at 21° C.was added methyl magnesium iodide (3M, Et2O, 0.3 mL, 0.9 mmol) dropwise.The resulting reaction mixture was stirred at 21° C. for 18 h, thendiluted with a saturated ammonium chloride solution and ethyl acetate.The organic extracts were washed (H₂O), (brine), dried (MgSO₄), filteredand concentrated. Purification by flash chromatography (eluting withtoluene/acetone, 85:15) provided the title compound as a mixture ofdiastereoisomers (5:1).

¹H NMR (400 MHz, acetone-d6): δ 8.87 (dd, 1H), 8.38 (dd, 1H), 8.20 (d,1H), 7.93 (d, 1H), 7.76-7.73 (m, 1H), 7.60 (d, 2H), 7.51 (dd, 1H),7.41-7.33 (m, 5H), 7.17 (d, 1H), 7.12 (t, 1H), 7.07 (d, 1H), 6.93 (t,1H), 4.50 (s, OH), 3.62 (dd, 1H), 3.54 (dd, 1H), 3.17 (t, 1H), 2.89 (s,3H), 2.69 (s, 3H), 1.95 (s, 6H), 1.78 (s, 3H). LRMS (CI) 646 (M+H)⁺.

EXAMPLE 191-(4-Fluoro-phenyl)-3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-2-methyl-propan-1-one

To a solution of Ketone 09 (171 g, 0.56 mmol) in THF (3 mL) at −20° C.was added potassium tert-butoxide (1M, 0.59 mL, 0.59 mmol) dropwisefollowed, after 15 min, by Quinoline 01 (250 mg, 0.59 mmol) dissolved inDMF (0.4 mL). The resulting reaction mixture was stirred at 21° C. for 3h and diluted with a saturated ammonium chloride solution and ethylacetate. The organic extracts were washed (H₂O), (brine), dried (MgSO₄),filtered and concentrated. Purification by flash chromatography (elutingwith toluene/acetone, 85:15) followed by stirring vigorously inhexane/ethyl acetate/ether for 1 h then filtered to afford the titlecompound as a white powder.

¹H NMR (400 Mz, acetone-d6): δ 8.90 (dd, 1H), 8.42 (dd, 1H), 8.23 (d,1H), 8.02 (d, 1H), 7.85 (d, 2H), 7.64-7.61 (m, 2H), 7.55 (dd, 1H), 7.50(d, 3H), 7.21 (d, 1H), 7.18 (s, 1H), 7.08-7.04 (m, 2H), 6.69 (d, 1H),3.54 (d, 1H), 3.46 (d, 1H); 2.84 (s, 3H), 2.71 (s, 3H), 1.97 (s, 6H),1.77 (s, 3H). LRMS (CI) 644 (M+H)⁺.

EXAMPLE 201-(3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-2,4,4-trimethyl-pentan-3-one

Following the procedures described in Example 19, but substitutingKetone 10 for Ketone 09 and purification by flash chromatography(eluting with dichloromethane/methanol, 99:1), then stirring vigorouslythe resulting solid in hexane/ethyl acetate/ether for 1 h and thenfiltration afforded the title compound as a white powder.

¹H NMR (400 MHz, acetone-d6): δ 8.91 (dd, 1H), 8.40 (dd, 1H), 8.22 (d,1H), 8.01 (d, 1H), 7.83 (d, 2H), 7.53 (dd, 1H), 7.46 (dd, 1H), 7.36 (dd,2H), 7.14 (t, 1H), 7.09 (s, 1H), 6.55 (s, 1H), 3.28 (d, 1H), 3.18 (d,1H), 2.81 (s, 3H), 2.70 (s, 3H), 1.97 (s, 3H), 1.96 (s, 3H), 1.77 (s,3H), 1.00 (s, 9H). LRMS (CI) 606 (M+H)⁺.

EXAMPLE 211-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-4,4-dimethyl-pentan-3-ol

To a solution of Example 06 (75 mg, 0.127 mmol) in MeOH (3 mL) at −78°C. was added sodium borohydride (5 mg, 0.13 mmol). The resultingreaction mixture was warmed to 21° C. then diluted with a saturatedammonium chloride solution and ethyl acetate. The organic extracts werewashed (H₂O), (brine), dried (MgSO₄), filtered and concentrated toprovide the title compound as a white foam (one pair of enantiomer).

¹H NMR (400 MHz, acetone-d6): δ 8.93 (dd, 1H), 8.45 (dd, 1H), 8.25 (d,1H), 8.07 (d, 1H), 7.78 (m, 4H), 7.59 (m, 2H), 7.49 (d, 1H), 7.31 (t,1H), 7.19 (d, 1H), 4.34 (d, OH), 3;66 (m, 1H), 3.45 (m, 1H), 3.29 (dd,1H), 3.09 (dd, 1H), 3.0 (s, 3H), 2.72 (s, 3H), 1.98 (s, 6H), 0.71 (s,9H). 99254-62.

EXAMPLE 221-(4-Fluoro-phenyl)-3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-propan-1-ol

Following the procedures described in Example 21, but substitutingExample 02 for Example 06 and purification by flash chromatography(eluting with dichloromethane/methanol, 99:1), then stirring vigorouslythe resulting residue in hexane/ethyl acetate/ether for 1 h and thenfiltration afforded the title compound as a white powder (one pair ofenantiomer).

¹H NMR (400 MHz, acetone-d₆): δ 8.90 (dd, 1H), 8.42 (dd, 1H), 8.23 (d,1H), 8.03 (d, 1H), 7.72 (d, 2H), 7.56-7.53 (m, 2H), 7.49-7.44 (m, 3H),7.31-7.23 (m, 3H), 7.18 (d, 1H), 7.00-6.95 (m, 2H), 5.11 (t, 1H), 4.65(d, OH), 3.53-3.50 (m, 1H), 3.27 (dd, 1H), 3.15 (d, 1H), 2.99 (s, 3H),2.70 (s, 3H), 1.97 (s, 6H).

EXAMPLE 232-(4-Fluoro-phenyl)-4-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-3-(4-methanesulfonyl-phenyl)-3-methyl-butan-2-ol

To a solution of Example 19 (93 mg, 0.144 mmol) in CH₂Cl₂ (4 mL) at −78°C. was added methyl magnesium iodide (3M, Et₂O, 0.24 mL, 0.8 mmol)dropwise. The resulting reaction mixture was stirred at 21° C. for 12 h,then diluted with a saturated ammonium chloride solution and ethylacetate. The organic extracts were washed (H₂O), (brine), dried (MgSO₄),filtered and concentrated. Purification by flash chromatography (elutingwith dichloromethane/methanol, 99:1, 2×), then stirring vigorously theresulting residue in hexane/ethyl acetate/ether for 1 h and thenfiltration afforded the title compound as a white powder (mixture ofdiastereoisomers; 1:1).

¹H NMR (400 MHz, acetone-d6): δ 8.87-8.80 (m, 2H), 8.41-8.35 (m, 2H),8.19-8.15 (m, 2H), 7.94 (d, 1H), 7.91 (d, 1H), 7.85-7.78 (m, 4H),7.70-7.66 (d, 2H), 7.61-7.35 (m, 11H), 7.21-7.08 (m, 4H), 7.05-6.98 (m,3H), 6.86-6.81 (m, 3H), 4.44 (d, 1H), 4.03 (d, 1H), 3.93 (d, 1H), 3.27(d, 1H), 2.96 (s, 3H), 2.94 (s, 3H), 2.68 (s, 3H), 2.67 (s, 3H),1.96-1.94 (m, 12H), 1.80 (s, 3H), 1.50 (s, 6H), 1.39 (s, 3H). LRMS (CI)660 (M+H)⁺.

EXAMPLE 244-{3-[6-(1-Methanesulfonyl-1-methylethyl)-quinolin-8-yl]-phenyl}-3-(4-methanesulfonyl-phenyl)-2-methyl-butan-2-ol

To a solution of Example 07 (230 mg, 0.41 mmol) in TBF/CH₂Cl₂ (1:1, 6mL) at 21° C. was added methyl magnesium bromide (3M, Et₂₀, 1.0 mL, 3mmol) dropwise. The resulting reaction mixture was stirred at 21° C. for0.25 h, then diluted with a saturated ammonium chloride solution andethyl acetate. The organic extracts were washed (H₂O), (brine), dried(MgSO₄), filtered and concentrated. Purification by flash chromatography(eluting with ethyl acetate/hexane, 70:30) afforded the title compoundas a white foam.

¹H NMR (400 MHz, acetone-d6): δ 8.88 (dd, 1H), 8.39 (dd, 1H), 8.21 (d,1H), 7.94 (d, 1H), 7.77 (d, 2H), 7.61 (d, 2H), 7.52 (dd, 1H), 7.41 (m,2H), 7.21 (t, 1H), 7.10 (d, 1H), 3.75 (s, OH), 3.52 (m, 3H), 3.26 (m,1H), 2.98 (s, 3H), 2.70 (s, 3H), 1.96 (s, 6H), 1.5 (s, 3H), 1.17 (s,3H).

EXAMPLE 251,1,1-Trifluoro-4-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-3-(4-methanesulfonyl-phenyl)-butan-2-ol

Step 1:3-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-propionaldehyde

Following the procedures described in Example 13, Step 2, butsubstituting Example 07 for the ester from Step 1, the3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-propionaldehydecompound was isolated as a white foam.

Step 2:1,1,1-Trifluoro-4-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-3-(4-methanesulfonyl-phenyl)-butan-2-ol

To a solution of3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-propionaldehydefrom Step 1 (413 mg, 0.8 mmol) in THF (10 mL) at −78° C. was addedTMSCF₃ (0.4 mL, 2.7 mmol) followed by tetrabutylammonium fluoride (1M,THF, 0.12 mL, 120 mmol). The resulting reaction mixture was warmed to 0°C., then quenched with tetrabutylammonium fluoride (1M, THF, 1 mL, 1mmol). After 1 h, the resulting solution was diluted with a saturatedammonium chloride solution and ethyl acetate. The organic extracts werewashed (H₂O), (brine), dried (MgSO₄), filtered and concentrated.Purification by flash chromatography (eluting with hexane/ethyl acetate,60:40 to 10:90) and sonication in hexane/ethyl acetate/ether providedthe1,1,1-trifluoro-4-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-3-(4-methanesulfonyl-phenyl)-butan-2-olcompound as a white powder (mixture of diastereoisomers).

¹H NMR (400 MHz, acetone-d6, major isomer): δ 8.91 (dd, 1H), 8.43 (dd,1H), 8.22 (d, 1H), 7.98 (d, 1H), 7.8 (m, 2H), 7.57 (m, 3H), 7.43 (s,1H), 7.23 (t, 1H), 7.04 (d, 1H), 5.88 (m, OH), 4.5 (m, 1H), 3.6 (m, 2H),3.2 (m, 1H), 3.04 (s, 3H), 1.97 (s, 6H).

EXAMPLE 262-Fluoro-3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methylsulfanyl-phenyl)-propionicacid ethyl ester

To a solution of Ester 03 (3.4 g, 13 mmol) and Quinoline 01 (4.5 g, 11mmol) in THF/DMF (2:1, 60 mL) at 0° C. was added potassium tert-butoxide(1M, THF, 13.9 mL, 13.9 mmol) dropwise. After 30 min. at 0° C., theresulting reaction mixture was diluted with a saturated ammoniumchloride solution and ethyl acetate. The organic extracts were washed(H₂O), (brine), dried (MgSO₄), filtered and concentrated. Purificationby flash chromatography (eluting with toluene/acetone, 9:1) provided thetitle compound.

¹H NMR (400 MHz, acetone-d₆): δ 8.91 (dd, 1H), 8.44 (dd, 1H), 8.26 (d,1H), 8.05 (d, 1H), 7.63-7.53 (m, 5H), 7.40-7.29 (m, 4H), 4.15 (q, 2H),3.80 (dd, 1H), 3.53 (dd, 1H), 2.70 (s, 3H), 2.49 (s, 3H), 1.99 (s, 6H),1.12 (t, 3H).

EXAMPLE 272-Fluoro-3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-propionicacid ethyl ester

Following the procedures described in Example 16, but substitutingExample 26 for Example 15, the title compound was obtained.

¹H NMR (400 MHz, acetone-d₆): δ 8.92 (dd, 1H), 8.44 (dd, 1H), 8.26 (d,1H), 8.06 (d, 1H), 8.01 (d, 2H), 7.90 (app d, 2H), 7.64-7.62 (m, 2H),7.56 (dd, 1H), 7.38 (t, 1H), 7.30 (d, 1H), 4.20 (q, 2H), 3.88 (dd, 1H),3.60 (dd, 1H), 3.10 (s, 3H), 2.71 (s, 3H), 1.99 (s, 6H), 1.19 (t, 3H).

EXAMPLE 282-Fluoro-3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-propan-1-ol

To a solution of Example 27 (1.15 g, 1.95 mmol) in CH₂Cl₂ (80 mL) at−78° C. was added dibal-H (0.82 mL, 4.6 mmol). The resulting reactionmixture was stirred 1 h at −78° C., then quenched with sodium potassiumtartrate solution and stirred at 21° C. for 3 h. The organic extractswere washed (H₂O), (brine), dried (MgSO₄), filtered and concentrated. Tothe residue dissolved in THF/MeOH (2:1, 22 mL) at 21° C. was added NaBH₄(180 mg, 4.9 mmol). After 12 h, the reaction mixture was diluted with asaturated ammonium chloride solution and ethyl acetate. The organicextracts were washed (H₂O), (brine), dried (MgSO₄), filtered andconcentrated to provided the title compound as a white solid.

¹H NMR (400 MHz, acetone-d₆): δ 8.90 (dd, 1H), 8.43 (dd, 1H), 8.24 (d,1H), 8.02 (d, 1H), 7.89 (d, 2H), 7.68 (d, 2H), 7.60-7.50 (m, 3H), 7.29(t, 1H), 7.15 (d, 1H), 4.42 (t, OH), 4.03 (dd, 11), 3.98 (dd, 1H), 3.58(dd, 1H), 3.44 (dd, 1H), 3.03 (s, 3H), 2.71 (s, 3H), 1.98 (s, 3H), 1.97(s, 3H).

EXAMPLE 293-Fluoro-4-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-3-(4-methanesulfonyl-phenyl)-2-methyl-butan-2-ol

Anhydrous CeCl₃ (658 mg, 2.67 mmol) was heated 1 h at 130° C. under highvacuum. It was refluxed in THF (8 mL) for 1 h and then cooled to 0° C.To the resulting white suspension at 0° C., was added methylmagnesiumbromide (3M, THF, 0.89 mL, 2.7 mmol). The resulting mixture was stirredat 0° C. for 1 h. Example 27 (267 mg, 0.45 mmol), dissolved in THF (1mL) was added, and the mixture stirred at 0° C. for 0.5 h, and dilutedwith ethyl acetate and saturated ammonium chloride solution. The organicextracts were washed (H₂O), (brine), dried (MgSO₄), filtered andconcentrated. Purification by flash chromatography (eluting withtoluene/acetone, 9:1) and stirring vigorously in ethyl acetate/ether for1 h, then filtering afforded the title compound as a white powder. Theenantiomers can be separated on a chiral column (ChiralPaK AD,hexane/EtOH, 50:50, retention time 6.82 and 9.27 min) to give Example29A and Example 29B.

¹H NMR (400 Mz, acetone-d₆): δ 8.88 (dd, 1H), 8.40 (dd, 1H), 8.21 (d,1H), 7.91 (d, 1H), 7.82 (d, 2H), 7.75 (app d, 2H), 7.53 (dd, 1H), 7.44(d, 1H), 7.41 (s, 1H), 7.17 (t, 1H), 7.11 (d, 1H), 4.29 (s, OH),3.77-3.54 (m, 2H), 2.96 (s, 3H), 2.70 (s, 3H), 1.97 (s, 3H), 1.96 (s,3H), 1.42 (s, 3H), 1.11 (s, 3H).

EXAMPLE 301-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-3-methyl-butane-2,3-diol

Following the procedures described in Example 29, but substitutingExample 17 for Example 27 and purification by flash chromatography(eluting with toluene/acetone, 80:20 afforded the title compound as awhite powder.

¹H NMR (400 MHz, acetone-d6): δ 8.88 (dd, 1H), 8.40 (dd, 1H), 8.21 (d,1H), 7.95 (d, 1H), 7.93 (d, 2H), 7.80 (d, 2H), 7.53 (dd, 1H), 7.50 (s,1H), 7.42 (dt, 1H), 7.18-7.12 (m, 2H), 4.08 (s, OH), 4.06 (s, OH), 3.75(d, 1H), 3.49 (d, 1H), 2.97 (s, 3H), 2.70 (s, 3H), 1.97 (s, 3H), 1.96(s, 3H), 1.25 (s, 3H), 1.20 (s, 3H). LRMS (CI) 582 (M+H)⁺.

EXAMPLE 312-Fluoro-3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-propionicacid

Following the procedures described in Example 08, but substitutingExample 27 for Example 07 and using only 1.5 equivalent of LiOH, thetitle compound was obtained as a white solid.

¹H NMR (400 MHz, acetone-d₆): δ 8.92 (dd, 1H), 8.44 (dd, 1H), 8.26 (d,1H), 8.06 (d, 1H), 8.01 (d, 2H), 7.92 (d, 2H), 7.66 (s, 1H), 7.63 (dd,1H), 7.56 (dd, 1H), 7.37 (t, 1H), 7.32 (d, 1H), 3.90 (dd, 1H), 3.62 (dd,1H), 3.10 (s, 3H), 2.72 (s, 3H), 1.99 (s, 3H), 1.99 (s, 3H).

EXAMPLE 323-Ethyl-2-fluoro-1-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-pentan-3-ol

Following the procedures described above in Example 29, but substitutingethylmagnesium bromide for methylmagnesium bromide and purification byflash chromatography (eluting with toluene/acetone, 9:1) afforded thetitle compound as a white foam.

¹H NMR (400 MHz, acetone-d6): δ 8.90 (dd, 1H), 8.41 (dd, 1H), 8.21 (d,1H), 7.92 (d, 1H), 7.81-7.75 (m, 4H), 7.54 (dd, 1H), 7.43 (d, 1H), 7.35(s, 1H), 7.16 (t, 1H), 7.05 (d, 1H), 4.07 (s, OH), 3.75-3.59 (m, 2H),2.93 (s, 3H), 2.71 (s, 3H), 2.01-1.90 (m, 2H), 1.98 (s, 3H), 1.97 (s,3H), 1.45-1.32 (m, 2H), 1.02 (dt, 3H), 0.82 (dt, 3H). LRMS (CI) 612(M+H)⁺.

EXAMPLE 331,1-Dicyclopropyl-2-fluoro-3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-propan-1-ol

Following the procedures described above in Example 29, but substitutingcyclopropyl magnesium bromide for methyl magnesium bromide andpurification by flash chromatography (eluting with toluene/acetone, 9:1)afforded the title compound as a white foam. The enantiomers can beseparated on a chiral column (ChiralPaK AD, hexane/i-PrOH/EtOH, 3:1:1,retention time 30 and 43 min) to give Example 33A and Example 33B.

¹H NMR (400 MHz, acetone-d6): δ 8.89 (dd, 1H), 8.39 (dd, 1H), 8.21 (d,1H), 7.92 (d, 1H), 7.83 (s, 4H), 7.52 (dd, 1H), 7.47 (s, 1H), 7.44 (dd,1H), 7.18-7.16 (m, 2H), 3.94 (dd, 1H), 3.87 (dd, 1H), 3.69 (s, OH), 2.97(s, 3H), 2.71 (s, 3H), 1.98 (s, 3H), 1.97 (s, 3H), 1.12-1.07 (m, 1H),0.91-0.86 (m, 1H), 0.69-0.64 (m, 1H), 0.53-0.49 (m, 1H), 0.43-0.29 (m,5H), 0.17-0.12 (m, 1H). LRMS (CI) 636 (M+H)⁺.

EXAMPLE 344-[2-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-(4-methanesulfonyl-phenyl)-ethyl]4,5,5-trimethyl-[1,3]dioxolan-2-one

Example 10 (236 mg, 0.39 mmol) and CDI (650 mg, 4 mmol) was heated at90° C. for 18 h, cooled to 21° C., and then diluted with ethyl acetateand sodium bicarbonate solution. The organic extracts were washed (H₂O),(brine), dried (MgSO₄), filtered and concentrated. Purification by flashchromatography (eluting with dichloromethane/ethyl acetate, 40:60)provided the title compound as a white solid (245 mg). The enantiomerscan be separated on a chiral column (ChiralPaK AD, hexane/i-PrOH, 40:60,retention time 10.7 and 12.6 min) to give Example 34A and Example 34B.

¹H NMR (400 MHz, acetone-d6): δ 8.89 (dd, 1H), 8.41 (dd, 1H), 8.21 (d,1H), 7.95 (d, 1H), 7.86 (d, 2H), 7.78 (d, 2H), 7.59 (s, 1H), 7.54 (dd,1H), 7.47 (d, 1H), 7.25 (t, 1H), 7.23 (d, 1H), 4.10 (dd, 1H), 3.47 (dd,1H), 3.16 (dd, 1H), 3.06 (s, 3H), 2.71 (s, 3H), 1.96 (s, 6H), 1.87 (s,3H), 1.71 (s, 3H), 1.48 (s, 3H).

EXAMPLE 355-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-4-(4-methanesulfonyl-phenyl)-2-methyl-pentane-2,3-diol

Following the procedures described above in Example 21, but substitutingExample 1 for Example 6 and using THF/EtOH as solvent. Purification byflash chromatography (eluting with dichloromethane/ethyl acetate, 40:60)afforded the title compound (one pair of enantiomer).

¹H NMR (400 MHz, acetone-d6): δ 8.93 (dd, 1H), 8.43 (dd, 1H), 8.24 (d,1H), 8.06 (d, 1H), 7.75 (dd, 4H), 7.60 (s, 1H), 7.56 (dd, 1H), 7.50 (d,1H), 7.31 (t, 1H), 7.20 (d, 1H), 4.12 (d, 1H), 3.81 (m, 1H), 3.50 (m,1H), 3.36 (dd, 1H), 3.26 (s, 1H), 3.10 (dd, 1H), 2.99 (s, 3H), 2.71 (s,3H), 1.98 (s, 6H), 1.03 (s, 3H), 0.87 (s, 3H).

EXAMPLE 362-Fluoro-4-hydroxy-1-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)₄-methyl-pentan-3-one

To a solution of Example 1 (200 mg, 0.34 mmol) in THF/DMF (1:1, 10 mL)at 0° C. was added potassium tert-butoxide (1M, THF, 0.34 mL, 0.34 mmol)dropwise. After 15 min, N-fluorobenzene sulfonimide (212 mg, 0.73 mmol)was added and the reaction mixture stirred for 2 h at 21° C. Theresulting mixture was diluted with a saturated ammonium chloridesolution and ethyl acetate. The organic extracts were washed (H₂O),(brine), dried (MgSO₄), filtered and concentrated. Purification by flashchromatography (eluting with toluene/acetone, 80:20) provided the titlecompound.

¹H NMR (400 MHz, acetone-d6): δ 8.93 (dd, 1H), 8.45 (dd, 1H), 8.29 (d,1H), 8.08 (d, 1H), 7.98 (d, 2H), 7.88 (d, 2H), 7.55 (m, 3H), 7.38 (t,1H), 7.26 (d, 1H), 4.22 (brs, 1H), 3.87 (dd, 1H), 3.42 (dd, 1H), 3.10(s, 3H), 2.71 (s, 3H), 1.98 (s, 6H), 1.17 (s, 3H), 1.12 (s, 3H).

EXAMPLE 374-Hydroxy-1-{3-[6-(1-methanesulfonyl-1-methylethyl)-quinolin-8-yl]-phenyl}-4-methyl-2-(4-methylsulfanyl-phenyl)-pentan-3-one

Following the procedures described in Example 1, but substituting Ketone01 for Ketone 02 and purification by flash chromatography (eluting withethyl acetate/hexane, 1:1 to 3:2) afforded the title compound as a whitefoam.

¹H NMR (400 Mz, acetone-d6): δ 8.92 (dd, 1H), 8.44 (dd, 1H), 8.25 (d,1H), 8.03 (d, 1H), 7.56 (dd, 1H), 7.51 (m, 2H), 7.33 (m, 3H), 7.2 (m,3H), 4.94 (dd, 1H), 4.31 (s, OH), 3.38 (dd, 1H), 3.00 (dd, 1H), 2.7 (s,3H), 2.44 (s, 3H), 1.98 (s, 6H), 1.07 (s, 3H), 1.03 (s, 3H).

EXAMPLE 382-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-(4-methanesulfonyl-phenyl)-ethanone

Step 1:(tert-Butyl-dimethyl-silanyloxy)-(4-methylsulfanyl-phenyl)-acetonitrile

To a solution of 4-methylthiobenzaldehyde (8 g, 52.5 mmol) inacetonitrile (260 mL) was added KCN (13.7 g, 210 mmol), ZnI₂ (335 mg, 1mmol) and t-BDMSCl (9.5 g, 63 mmol). After 18 h, the resulting reactionmixture was filtered and the mother liquors concentrated. The resultingresidue was left overnight under high vacuum to provided the(tert-butyl-dimethyl-silanyloxy)-(4-methylsulfanyl-phenyl)-acetonitrilecompound as a clear oil.

Step 2:2-(tert-Butyl-dimethyl-silanyloxy)-3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methylsulfanyl-phenyl)-propionitrile

To a solution of(tert-butyl-dimethyl-silanyloxy)-(4-methylsulfanyl-phenyl)-acetonitrilefrom Step 1 above (1.52 g, 5.2 mmol) in THF (25 mL) at −78° C. was addedKHMDS (1M, 5.2 mL, 5.2 mmol) dropwise followed, after 10 min, byQuinoline 01 (1.8 g, 4.3 mmol) in THF (25 mL). The resulting reactionmixture was allowed to warm to −10° C. and diluted with a sodiumbicarbonate solution and ethyl acetate. The organic extracts were washed(H₂O), (brine), dried (MgSO₄), filtered and concentrated.

Step 3:2-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-(4-methylsulfanyl-phenyl)-ethanone

To a solution of crude cyanohydrin from Step 2 above in THF (25 mL) wasadded tetrabutylammonium fluoride (1M, THF, 6.5 mL, 6.5 mmol) dropwise.The resulting reaction mixture was stirred at 21° C. for 30 min anddiluted with a sodium hydroxide solution and ethyl acetate. The organicextracts were washed (1N NaOH 2×), (brine), dried (MgSO₄), filtered andconcentrated.

Step 4:2-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)quinolin-8-yl]-phenyl}-1-(4-methanesulfonyl-phenyl)-ethanone

Following the procedures described above in Example 16, but substitutingthe2-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-(4-methylsulfanyl-phenyl)-ethanonefrom step 3 for Example 15, the2-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-(4-methanesulfonyl-phenyl)-ethanonecompound was obtained as a foam.

¹H NMR (400 MHz, acetone-d₆): δ 8.89 (dd, 1H), 8.44 (dd, 1H), 8.35 (d,2H), 8.26 (d, 1H), 8.10-8.08 (m, 3H), 7.72 (s, 1H), 7.63 (d, 2H), 7.56(dd, 1H), 7.44 (t, 1H), 7.38 (d, 1H), 4.57 (s, 2H), 3.17 (s, 3H), 2.70(s, 3H), 1.98 (s, 6H).

EXAMPLE 392-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-(4-methanesulfonyl-phenyl)-ethanol

Following the procedures described above in Example 21, but substitutingExample 38 for Example 6 and using THF/MeOH as solvent. The resultingresidue was stirred vigorously in ethyl acetate/ether for 1 h thenfiltered to afford the title compound as a white powder.

¹H NMR (400 MHz, acetone-d₆): δ 8.91 (dd, 1H), 8.44 (dd, 1H), 8.26 (d,1H), 8.09 (d, 1H), 7.88 (d, 2H), 7.61-7.53 (m, 3H), 7.59 (d, 2H), 7.36(t, 1H), 7.27 (app d, 1H), 5.62 (app t, 1H), 4.67 (d, OH), 3.11 (d, 2H),3.06 (s, 3H), 2.72 (s, 3H), 1.98 (s, 6H).

EXAMPLE 404-[2-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-(4-methanesulfonyl-phenyl)-ethylsulfanyl]-benzoicacid ethyl ester

To a solution of Example 39 (283 mg, 0.54 mmol), Ph₃P (283 mg, 1.08mmol) and DEAD (0.17 mL, 1.08 mmol) in THF (3 mL) at 0° C., was slowlyadded ethyl 4-mercaptobenzoate (200 mg, 1.08 mmol, over 20 min.) in DMF(2 mL). The reaction mixture was stirred at 0° C. 1 h, at 21° C. for 18h, then diluted with water and ethyl acetate. The organic extracts werewashed (H₂O), (brine), dried (MgSO₄), filtered and concentrated.Purification by flash chromatography (eluting with hexane/ethyl acetate,1:1) provided the title compound as an oil.

¹H NMR (400 MHz, acetone-d₆): δ 8.92 (dd, 1H), 8.44 (dd, 1H), 8.25 (d,1H), 8.05 (d, 1H), 7.85-7.81 (m, 4H), 7.74 (dd, 2H), 7.62 (s, 1H),7.58-7.55 (m, 2H), 7.45 (dd, 2H), 7.32 (t, 1H), 7.23 (d, 1H), 5.13 (dd,1H), 4.28 (q, 2H), 3.47-3.38 (m, 2H), 3.01 (s, 3H), 2.72 (s, 3H), 1.98(s, 6H), 1.31 (t, 3H).

EXAMPLE 412-{4-[2-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-(4-methanesulfonyl-phenyl)-ethylsulfanyl]-phenyl}-propan-2-ol

A solution of Example 40 (280 mg, 0.4 mmol) and anhydrous CeCl₃ (150 mg,0,5 mmol) in THF (5 mL) was stirred at 21° C. for 1 h, then cooled at−78° C. Methylmagnesium bromide (3M, Ether, 0.6 mL, 2.1 mmol) was addedand the resulting reaction mixture warmed slowly to 0° C., then dilutedwith a saturated ammonium chloride solution and ethyl acetate. Theorganic extracts were washed (H₂O), (brine), dried (MgSO₄), filtered andconcentrated. Purification by flash chromatography (eluting withhexane/ethyl acetate, 1:1 to 2:8) provided the title compound as asolid.

¹H NMR (400 MHz, acetone-d₆): δ 8.91 (dd, 1H), 8.44 (dd, 1H), 8.24 (d,1H), 8.04 (d, 1H), 7.79 (s, 2H), 7.71-7.53 (m, 5H), 7.41 (d, 2H),7.32-7.28 (m, 3H), 7.19 (d, 1H), 4.88 (dd, 1H), 4.02 (s, OH), 3.45-3.34(m, 2H), 3.01 (s, 3H), 2.71 (s, 3H), 1.97 (s, 6H), 1.44 (s, 6H).

EXAMPLE 422-{4-[2-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-(4-methanesulfonyl-phenyl)-ethanesulfonyl]-phenyl}-propan-2-ol

Following the procedures described above in Example 16, but substitutingExample 41 for Example 15 and purification by stirring vigorously theresulting solid in hexane/ethyl acetate/ether for 1 h and thenfiltration afforded the title compound as a white powder.

¹H NMR (400 MHz, acetone-d₆): δ 8.86 (dd, 1H), 8.41 (dd, 1H), 8.22 (d,1H), 7.93 (d, 1H), 7.79 (d, 2H), 7.71-7.51 (m, 8H), 7.71 (d, 1H), 7.47(d, 1H), 7.24 (t, 1H), 5.07 (dd, 1H), 4.33 (s, OH), 3.75 (dd, 1H), 3.62(dd, 1H), 3.05 (s, 3H), 2.70 (s, 3H), 1.95 (s, 6H), 1.50 (s, 3H), 1.50(s, 3H).

EXAMPLE 432-{4-[1-Fluoro-2-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-(4-methanesulfonyl-phenyl)-ethanesulfonyl]-phenyl}-propan-2-ol

By following the procedures described above in Example 36, butsubstituting Example 42 for Example 1, the title compound was obtainedas a white solid.

¹H NMR (400 MHz, acetone-d₆): δ 8.84 (dd, 1H), 8.41 (dd, 1H), 8.22 (d,1H), 7.92 (d, 1H), 7.86 (d, 2H), 7.71-7.51 (m, 9H), 7.26 (t, 1H), 7.20(d, 1H), 4.38 (s, OH), 4.19 (dd, 1H), 3.88 (dd, 1H), 3.07 (s, 3H), 2.69(s, 3H), 1.96 (s, 3H), 1.94 (s, 3H), 1.51 (s, 3H), 1.50 (s, 3H).

EXAMPLE 448-{3-[2-Fluoro-2-methanesulfonyl-2-(4-methanesulfonyl-phenyl)-ethyl]-phenyl}-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

Example 44 was prepared by following the procedures described above inExample 1, but substituting Sulfone 02 for Ketone 02, and using DMF assolvent. Purification by flash chromatography (eluting with ethylacetate/hexane, 95:5 to 100:0), then stirring vigorously the resultingsolid in ether/ethyl acetate for 1 h and filtration afforded the titlecompound as a white powder. The enantiomers can be separated on a chiralcolumn (ChiralPaK AD, hexane/EtOH/i-PrOH/MeOH, 30:30:30:10, retentiontime 10.0 and 12.5 min) to give Example 44A and Example 44B.

¹H NMR (400 Mz, ace-d6): δ 8.90 (dd, 1H), 8.42 (dd, 1H), 8.24 (d, 1H),7.98 (d, 1H), 7.93 (d, 2H), 7.85 (d, 2H), 7.57 (app d, 1H), 7.55 (dd,1H), 7.50 (app d, 1H), 7.30 (t, 1H), 7.24 (app d, 1H), 5.01 (dd, 1H),3.87 (dd, 1H), 3.55 (dd, 1H), 3.07 (s, 3H), 2.88 (s, 3H), 2.70 (s, 3H),1.97 (s, 6H).

EXAMPLE 458-{3-[2-Methanesulfonyl-2-(4-methanesulfonyl-phenyl)-ethyl]-phenyl}-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

Example 45 was prepared by following the procedures described above inExample 1, but substituting Sulfone 01 for Ketone 02, and using DMF assolvent. Purification by flash chromatography (eluting with ethylacetate/hexane, 80:20 to 100:0), then stirring vigorously the resultingsolid in ethyl acetate/ether for 1 h and filtration afforded the titlecompound as a white powder.

¹H NMR (400 MHz, acetone-d₆): δ 8.90 (dd, 1H), 8.43 (dd, 1H), 8.24 (d,1H), 7.98 (d, 1H), 7.93 (d, 2H), 7.85 (d, 2H), 7.57 (app d, 1H), 7.55(dd, 1H), 7.50 (d, 1H), 7.30 (t, 1H), 7.24 (d, 1H), 5.01 (dd, 1H), 3.87(dd, 1H), 3.54 (dd, 1H), 3.07 (s, 3H), 2.88 (s, 3H), 2.70 (s, 3H), 1.97(s, 6H).

EXAMPLE 468-{3-[2-Ethanesulfonyl-2-fluoro-2-(4-methanesulfonyl-phenyl)-ethyl]-phenyl}-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

Step 1:8-{3-[2-Ethanesulfonyl-2-(4-methanesulfonyl-phenyl)-ethyl]-phenyl}-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

The procedures described above in Example 01 were followed, but Sulfone04 was substituted for Ketone 02, and THF was used as the solvent.Purification by flash chromatography (eluting with ethyl acetate/hexane,80:20 to 100:0), then stirring vigorously the resulting solid in ethylacetate/ether for 1 h and filtration afforded the8-{3-[2-ethanesulfonyl-2-(4-methanesulfonyl-phenyl)-ethyl]-phenyl}-6-(1-methanesulfonyl-1-methyl-ethyl)-quinolinecompound as a white powder.

Step 2:8-{3-[2-Ethanesulfonyl-2-fluoro-2-(4-methanesulfonyl-phenyl)-ethyl]-phenyl}-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

Following the procedures described in Example 36, but substituting8-{3-[2-ethanesulfonyl-2-(4-methanesulfonyl-phenyl)-ethyl]-phenyl}-6-(1-methanesulfonyl-1-methyl-ethyl)-quinolinefrom Step 1 above for Example 1, the8-{3-[2-ethanesulfonyl-2-fluoro-2-(4-methanesulfonyl-phenyl)-ethyl]-phenyl}-6-(1-methanesulfonyl-1-methyl-ethyl)-quinolinecompound was obtained as a white solid.

¹H NMR (400 MHz, ace-d6): δ 8.89 (dd, 1H), 8.42 (dd, 1H), 8.23 (d, 1H),8.01 (d, 2H), 7.96-7.92 (m, 3H), 7.57-7.53 (m, 3H), 7.29 (t, 1H), 7.21(app d, 1H), 4.04 (m, 2H), 3.22-3.15 (m, 1H), 3.07 (s, 3H), 3.00-2.91(m, 1H), 2.70 (s, 3H), 1.97 (s, 3H), 1.96 (s, 3H), 1.26 (t, 3H).

EXAMPLE 476-(1-Methanesulfonyl-1-methyl-ethyl)-8-{3-[2-(4-methanesulfonyl-phenyl)-2-(1-methyl-1H-imidazole-2-sulfonyl)-ethyl]-phenyl}-quinoline

Example 47 was prepared by following the procedures described above inExample 1, but substituting Sulfone 05 for Ketone 02, and using THF assolvent. Purification by flash chromatography (eluting with ethylacetate), then stirring vigorously the resulting solid in ethylacetate/ether for 1 h and filtration afforded the title compound as awhite powder.

¹H NMR (400 MHz, ace-d6): δ 8.91 (dd, 1H), 8.42 (dd, 1H), 8.24 (d, 1H),7.98 (d, 1H), 7.93 (d, 2H), 7.85 (d, 2H), 7.57 (d, 1H), 7.55 (dd, 1H),7.50 (d, 1H), 7.30 (t, 1H), 7.24 (d, 1H), 5.01 (dd, 1H), 3.87 (dd, 1H),3.55 (dd, 1H), 3.07 (s, 3H), 2.88 (s, 3H), 2.70 (s, 3H), 1.97 (s, 6H).

EXAMPLE 488-{3-[2-Fluoro-2-(4-methanesulfonyl-phenyl)-2-(1-methyl-1H-imidazole-2-sulfonyl)-ethyl]-phenyl}-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

By following the procedures described above in Example 36, butsubstituting Example 47 for Example 1, the title compound was obtainedas a white solid.

¹H NMR (400 MHz, ace-d6): δ 8.85 (dd, 1H), 8.41 (dd, 1H), 8.22 (d, 1H),7.97 (d, 2H), 7.93 (d, 1H), 7.77 (d, 1H), 7.55-7.52 (m, 3H), 7.49 (s,1H), 7.27 (t, 1H), 7.21 (s, 1H), 7.19 (app d, 1H), 4.23 (d, 1H), 3.95(dd, 1H), 3.79 (s, 3H), 3.11 (s, 3H), 2.70 (s, 3H), 1.96 (s, 3H), 1.95(s, 3H).

EXAMPLE 498-{3-[2-Fluoro-2-(4-methanesulfonyl-phenyl)-2-(thiazole-2-sulfonyl)-ethyl]-phenyl}-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

By following the procedures described above in Example 46, butsubstituting Sulfone 06 for Sulfone 04 in Step 1, the title compound wasobtained as a white solid.

¹H NMR (400 MHz, ace-d6): δ 8.85 (dd, 1H), 8.41 (dd, 1H), 8.31 (d, 1H),8.22 (d, 1H), 8.20 (d, 1H), 7.97-7.93 (m, 3H), 7.82 (d, 2H), 7.56-7.52(m, 3H), 7.28 (t, 1H), 7.21 (app d, 1H), 4.30 (dd, 1H), 4.10 (dd, 1H),3.09 (s, 3H), 2.70 (s, 3H), 1.96 (s, 3H), 1.95 (s, 3H.

EXAMPLE 504-Hydroxy-2-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-1-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}4-methyl-pentan-3-one

By following the procedures described above in Example 1, butsubstituting Ketone 11 for Ketone 02, the title compound was obtained asa white foam.

¹H NMR (400 MHz, acetone-d6): δ 8.93 (dd, 1H), 8.44 (dd, 1H), 8.26 (d,1H), 8.07 (d, 1H), 7.58 (m, 2H), 7.49 (d, 1H), 7.45 (d, 2H), 7.35 (m,3H), 7.22 (d, 1H), 4.97 (dd, 1H), 4.27 (s, OH), 3.94 (s, OH), 3.38 (dd,1H), 2.99 (dd, 1H), 2.71 (s, 3H), 1.99 (s, 6H), 1.46 (s, 6H), 1.04 (s,3H), 1.00 (s, 3H).

EXAMPLE 514-[4-(1-Hydroxy-1-methyl-ethyl)-phenyl]-5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-methyl-pentane-2,3-diol

By following the procedures described above in Example 21, butsubstituting Example 50 for Example 6 and using EtOH as solvent, thetitle compound was obtained as a white foam.

¹H NMR (400 MHz, acetone-d6): δ 8.93 (dd, 1H), 8.43 (dd, 1H), 8.24 (d,1H), 8.09 (d, 1H), 7.65 (s, 1H), 7.56 (dd, 1H), 7.52 (d, 1H), 7.45-7.32(m, 4H), 7.32 (t, 1H), 7.23 (d, 1H), 3.86 (s, OH), 3.71 (m, 2H), 3.30(m, 2H), 3.01 (m, 2H), 2.71 (s, 3H), 1.99 (s, 6H), 1.45 (s, 6H), 1.05(s, 3H), 0.78 (s, 3H).

EXAMPLE 522-[4-(1-Methanesulfonyl-2-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-ethyl)-phenyl]-propan-2-ol

By following the procedures described above in Example 1, butsubstituting Sulfone 07 for Ketone 02, the title compound was obtainedas a white foam.

¹H NMR (400 MHz, acetone-d6): δ 8.90 (dd, 2H), 8.42 (dd, 2H), 8.24 (d,1H), 8.00 (d, 1H), 7.59 (s, 1H), 7.55 (dd, 1H), 7.51 (m, 5H), 7.29 (t,1H), 7.21 (d, 1H), 4.75 (dd, 1H), 3.99 (s, OH), 3.81 (dd,), 3.49 (dd,1H), 2.74 (s, 3H), 2.7 (s, 3H), 1.97 (s, 6H), 1.44 (s, 6H).

EXAMPLE 53[2-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-(4-methanesulfonyl-phenyl)-ethyl]-phosphonicacid dimethyl ester

By following the procedures described above in Example 1, butsubstituting Phosphonate 01 for Ketone 02 and purification by flashchromatography (eluting with toluene/acetone, 50:50), the title compoundwas obtained as a white foam.

¹H NMR (400 MHz, acetone-d6): δ 8.89 (dd, 1H), 8.40 (dd, 1H), 8.23 (d,1H), 8.01 (d, 1H), 7.84 (d, 2H), 7.71 (d, 2H), 7.50 (m, 3H), 7.26 (s,1H), 7.19 (d, 1H), 3.90 (m, 1H), 3.71 (d, 3H), 3.57 (d, 3H), 3.55 (m,1H), 3.40 (m, 1H), 3.02 (s, 3H), 2.70 (s, 3H), 1.98 (s, 6H).

EXAMPLE 548-{3-[2-(5,5-Dimethyl-2-oxo-2λ⁵-[1,3,2]dioxaphosphinan-2-yl)-2-(4-methanesulfonyl-phenyl)-ethyl]-phenyl}-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

By following the procedures described above in Example 1, butsubstituting Phosphonate 03 for Ketone 02 and purification by flashchromatography (eluting with toluene/acetone, 60:40), the title compoundwas obtained as a white foam.

¹H NMR (400 MHz, acetone-d6): δ 8.90 (dd, 1H), 8.42 (dd, 1H), 8.24 (d,1H), 8.00 (d, 1H), 7.84 (d, 2H), 7.73 (d, 2H), 7.53 (m, 3H), 7.27 (t,1H), 7.18 (d, 1H), 4.20 (m, 3H), 4.03 (m, 1H), 3.92 (m, 1H), 3.57 (m,1H), 3.40 (m, 1H), 3.06 (s, 3H), 2.72 (s, 3H), 1.97 (s, 6H), 1.13 (s,3H), 0.91 (s, 3H).

EXAMPLE 55[1-Fluoro-2-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-(4-methanesulfonyl-phenyl)-ethyl]-phosphonicacid dimethyl ester

By following the procedures described above in Example 1, butsubstituting Phosphonate 02 for Ketone 02 and purification by flashchromatography (eluting with toluene/acetone, 60:40), the title compoundwas obtained as a white foam.54 corrected ¹H NMR (400 MHz, acetone-d6):δ 8.88 (dd, 1H), 8.41 (dd, 1H), 8.22 (d, 1H), 7.96 (d, 1H), 7.92 (d,2H), 7.78 (d, 2H), 7.53 (m, 2H), 7.49 (s, 1H), 7.28 (t, 1H), 7.14 (s,1H), 3.84 (d, 3H), 3.83 (m, 2H), 3.58 (d, 3H), 3.02 (s, 3H), 2.70 (s,3H), 1.97 (s, 3H), 1.96 (s, 3H).

EXAMPLE 568-{3-[2-(5,5-Dimethyl-2-oxo-2λ⁵-[1,3,2]dioxaphosphinan-2-yl)-2-fluoro-2-(4-methanesulfonyl-phenyl)-ethyl]-phenyl}-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

By following the procedures described above in Example 36, butsubstituting Example 54 for Example 1 and purification by flashchromatography (eluting with toluene/acetone, 75:25), the title compoundwas obtained as a white foam.

¹H NMR (400MHz, acetone-d6): δ 8.90 (dd, 1H), 8.41 (dd, 1H), 8.22 (d,1H), 7.98 (d, 1H), 7.93 (d, 2H), 7.80 (d, 2H), 7.53 (m, 2H), 7.48 (s,1H), 7.26 (t, 1H), 7.14 (d, 1H), 4.53 (dd, 1H), 4.38 (dd, 1H), 4.14 (m,1H), 3.96 (m, 1H), 3.89 (m, 1H), 3.72 (m, 1H), 3.02 (s, 3H), 2.70 (s,3H), 1.97 (s, 6H), 1.25 (s, 3H), 0.93 (s, 3H).

EXAMPLE 578-{3-[2-[Bis-(2,2,2-trifluoro-ethyl)-phosphinoyl]-2-fluoro-2-(4-methanesulfonyl-phenyl)-ethyl]-phenyl}-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

Following the procedures described above in Example 46, but substitutingPhosphonate 04 for Sulfone 04 and purification by flash chromatography(eluting with toluene/acetone, 70:30), afforded the title compound as awhite foam.

¹H NMR (400 MHz, acetone-d6): δ 8.90 (dd, 1H), 8.45 (m, 1H), 8.29 (m,1H), 8.25 (d, 1H), 8.10 (d, 1H), 7.95 (d, 2H), 7.85 (d, 1H), 7.59 (m,3H), 7.33 (t, 1H), 7.27 (d, 1H), 4.78 (m, 1H), 4.59 (m, 2H), 4.39 (m,1H), 3.85 (m, 2H), 3.05 (s, 3H), 2.71 (s, 3H), 1.98 (s, 6H).

EXAMPLE 582-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-(4-methanesulfonyl-phenyl)-ethanesulfonicacid dimethylamide

By following the procedures described above in Example 1, butsubstituting Sulfone 08 for Ketone 02, the title compound was obtainedas a white foam.

¹H NMR (400 MHz, acetone-d6): δ 8.88 (dd, 1H), 8.39 (dd, 1H), 8.22 (d,1H), 7.97 (d, 1H), 7.93 (d, 2H), 7.86 (d, 2H), 7.55-7.50 (m, 3H),7.29-7.19 (m, 2H), 5.03 (dd, 1H), 3.75 (dd, 1H), 3.57 (dd, 1H), 3.05 (s,3H), 2.70 (s, 3H), 2.67 (s, 6H), 1.96 (s, 6H).

EXAMPLE 591-Fluoro-2-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-(4-methanesulfonyl-phenyl)-ethanesulfonicacid dimethylamide

By following the procedures described above in Example 36, butsubstituting Example 58 for Example 1, the title compound was obtainedas a white solid.

¹H NMR (400 MHz, acetone-d₆): δ 8.98 (d, 11H), 8.88 (dd, 1H), 8.18 (dd,1H), 7.90 (d, 2H), 7.81 (d, 3H), 7.48 (d, 1H), 7.41 (dd, 1H), 7.39 (s,1H), 7.25 (t, 1H), 7.07 (d, 1H), 3.96-3.80 (m, 2H), 2.95 (s, 3H), 2.68(br s, 6H), 2.60 (s, 3H), 1.944 (s, 3H), 1.936 (s, 3H).

EXAMPLE 608-{3-[1-(4-Chloro-phenyl)-2-pyridin-4-yl-ethyl]-phenyl}-6-isopropyl-quinoline

Step 1:(4-Chloro-phenyl)-[3-(6-isopropyl-quinolin-8-yl)-phenyl]-methanol

To a solution of Quinoline 04 (1.0 g, 3.6 mmol) in CH₂Cl₂ (5 mL) at −10°C. was added 4-chlorophenylmagnesium bromide (0.7M, THF, 5 mL, 7 mmol)dropwise. After 1 h, a saturated ammonium chloride solution was addedand the reaction mixture extracted with CH₂Cl₂ (3×). The organicextracts were washed (H₂O, brine), dried (MgSO₄), filtered andconcentrated. Purification by flash chromatography (eluting withhexane/ethyl acetate, 70:30) provided the(4-chloro-phenyl)-[3-(6-isopropyl-quinolin-8-yl)-phenyl]-methanolcompound as a white solid.

Step 2:8-{3-[Chloro-(4-chloro-phenyl)-methyl]-phenyl}-6-isopropyl-quinoline

To a solution of(4-chloro-phenyl)-[3-(6-isopropyl-quinolin-8-yl)-phenyl]-methanol fromStep 1 (1.0 g, 2.58 mmol) in benzene (7 mL) at 0° C. was added SOCl₂(0.375 mL, 5.2 mmol) dropwise. After 45 min. at 0-10° C., the resultingreaction mixture was filtered through silica gel and celite and thenconcentrated.

Step 3:3-(4-Chloro-phenyl)-3-[3-(6-isopropyl-quinolin-8-yl)-phenyl]-2-pyridin-4-yl-propionicacid ethyl ester

To a solution of ethyl 4-pyridinylacetate (1.28 g, 7.74 mmol) inTHF/HMPA (3:1, 5 mL) at −10° C. was added NaHMDS (1M, 7.8 mL, 7.8 mmol)dropwise. After 60 min., the crude chloride from Step 2 above was addedand the resulting reaction mixture was stirred for 18 h at 21° C., andthen diluted with a saturated ammonium chloride solution and ethylacetate. The organic extracts were washed (H₂O, brine), dried (MgSO₄),filtered and concentrated.

Step 4:8-{3-[1-(4-Chloro-phenyl)-2-pyridin-4-yl-ethyl]-phenyl}-6-isopropyl-quinoline

To a solution of the crude ester from Step 3 above in THF/EtOH (10 mL)was added NaOH (2N, 2 mL). The resulting reaction mixture was stirred 18h at 100° C. then neutralized with HCl 6N to pH 7 and diluted with ethylacetate. The organic extracts were washed (H₂O, brine), dried (MgSO₄),filtered and concentrated. Purification by flash chromatography (elutingwith hexane/ethyl acetate, 1:1) provided the8-{3-[1-(4-chloro-phenyl)-2-pyridin-4-yl-ethyl]-phenyl}-6-isopropyl-quinolinecompound.

¹H NMR (500 MHz, acetone-d6): δ 8.81 (dd, 1H), 8.36 (d, 2H), 8.30 (dd,1H), 7.76 (d, 2H), 7.6 (s, 1H), 7.51 (d, 1H), 7.46 (m, 3H), 7.33 (m,4H), 7.22 (d, 2H), 4.53 (t, 1H), 3.52 (m, 2H), 3.15 (m, 1H), 1.39 (s,6H).

EXAMPLE 618-{3-[1-(4-Chloro-phenyl)-2-(1-oxy-pyridin-4-yl)-ethyl]-phenyl}-6-isopropyl-quinoline

To a solution of Example 60 (100 mg, 0.22 mmol) in CH₂Cl₂/MeOH (1:1, 6mL) was added MMPP (320 mg, 0.65 mmol). After 18 h, the resultingreaction mixture was diluted with a sodium bicarbonate solution andethyl acetate. The organic extracts were washed (H₂O, brine), dried(MgSO₄), filtered and concentrated. Purification by flash chromatography(eluting with ethanol/ethyl acetate, 10:90 to 25:75) provided the titlecompound.

¹H NMR (500 MHz, acetone-d6): δ 8.83 (dd, 1H), 8.30 (dd, 1H), 7.95 (d,2H), 7.76 (d, 2H), 7.63 (s, 1H), 7.48 (m, 4H), 7.35 (m, 4H), 7.22 (d,2H), 4.49 (t, 1H), 3.52 (m, 2H), 3.18 (m, 1H), 1.39 (s, 6H).

EXAMPLE 628-{3-[1-(4-Chloro-phenyl)-2-pyridin-4-yl-ethyl]-phenyl}-quinoline

Step 1: 4-[2-(3-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-pyridine

Following the procedures described above in Example 60, but substituting3-bromobenzaldehyde for Quinoline 04 and purification by flashchromatography (eluting with hexane/ethyl acetate, 4:1) afforded the4-[2-(3-bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-pyridine compound.

Step 2:8-{3-[1-(4-Chloro-phenyl)-2-pyridin-4-yl-ethyl]-phenyl}-quinoline

A solution of 4-[2-(3-bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-pyridinefrom Step 1 above (400 mg, 1.07 mmol), diboron pinacol ester (300 mg,1.18 mmol), KOAc (315 mg, 3.2 mmol) and PdCl₂(dppf) (26 mg, 0.032 mmol)in DMF (20 mL) was heated at 80° C. under N₂ for 5 h. The resultingreaction mixture was cooled to 21° C., 8-bromoquinoline (290 mg, 1.4mmol), Na₂CO₃ (2M, 1.61 mL, 3.2 mmol) and PdCl₂(dppf) (26 mg, 0.032mmol) was then added. The reaction mixture was stirred 18 h at 80° C.,then diluted with a saturated ammonium chloride solution and ethylacetate. The organic extracts were washed (H₂O, brine), dried (MgSO₄),filtered and concentrated. Purification by flash chromatography (elutingwith hexane/ethyl acetate, 50:50 to 25:75) provided the8-{3-[1-(4-chloro-phenyl)-2-pyridin-4-yl-ethyl]-phenyl}-quinolinecompound (319 mg).

¹H NMR (500 MHz, acetone-d6): δ 8.88 (dd, 1H), 8.37 (d, 1H), 8.36 (d,2H), 7.95 (dd, 1H), 7.76 (s, 1H), 7.71 (dd, 1H), 7.64 (t, 1H), 7.52 (m,2H), 7.48 (d, 2H), 7.37 (d, 2H), 7.28 (d, 2H), 7.21 (d, 2H), 4.51 (t,1H), 3.52 (m, 2H).

EXAMPLE 638-{3-[1-(4-Chloro-phenyl)-2-(1-oxy-pyridin-4-yl)-ethyl]-phenyl}-quinoline

Following the procedures described above in Example 61, but substitutingExample 62 for Example 60, the title compound was obtained.

¹H NMR (500 Mz, acetone-d6): δ 8.90 (dd, 1H), 8.38 (dd, 1H), 7.94 (m,3H), 7.72 (t, 2H), 7.65 (t, 1H), 7.52 (m, 2H), 7.48 (d, 2H), 7.32 (m,4H), 7.21 (d, 2H), 4.48 (t, 1H), 3.50 (m, 2H).

EXAMPLE 64 6-Isopropyl-8-[3-(2-pyridin-4-yl-ethyl)-phenyl]-quinoline

Using 3-bromobenzyl chloride as the starting material, and following theprocedures described above in Example 60, Steps 3 and 4, followed byprocedures described in Example 62, Step 2, the title compound wasobtained.

¹H NMR (300 MHz, acetone-d6): δ 8.80 (dd, 1H), 8.44 (dd, 2H), 8.29 (dd,1H), 7.76 (d, 1H), 7.63 (d, 1H), 7.52 (s, 2H), 7.46 (q, 1H), 7.25 (t,1H), 7.25 (d, 3H), 3.16 (m, 1H), 3.01 (s, 4H), 1.38 (d, 6H).

EXAMPLE 656-Isopropyl-8-{3-[2-(1-oxy-pyridin-4-yl)-ethyl)-phenyl}-quinoline

Following the procedures described in Example 61, but substitutingExample 64 for Example 60, the title compound was obtained.

¹H NMR (500 MHz, acetone-d6): δ 8.82 (dd, 1H), 8.30 (dd, 1H), 8.01 (d,2H), 7.76 (d, 1H), 7.65 (d, 1H), 7.52 (s&dd, 2H), 7.48 (q, 1H), 7.36 (t,1H), 7.24 (d, 3H), 3.17 (m, 1H), 3.01 (s, 4H), 1.36 (s, 6H).

EXAMPLE 663-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-pyridin-4-yl-propionic acidethyl ester

Using 3-bromobenzyl chloride as the starting material, and following theprocedures described in Example 60, Step 3, followed by proceduresdescribed in Example 62, Step 2, the title compound was obtained as anoil.

¹H NMR (500 MHz, acetone-d6): δ 8.82 (s, 1H), 8.52 (d, 2H), 8.28 (dd,1H), 7.78 (d, 1H), 7.58 (d, 2H), 7.49 (t, 2H), 7.38 (m, 3H), 7.21 (d,1H), 4.05 (q, 1H), 3.48 (q, 2H), 3.1 (q, 2H), 1.38 (d, 6H), 1.1 (t, 3H).

EXAMPLE 673-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-pyridin-4-yl-propan-1-ol

To a solution of Example 66 (15 mg, 0.035 mmol) in THF (mL) at 0° C. wasadded LiAlH₄ (1M, THF, 0.35 mL, 0.35 mmol) dropwise. The resultingreaction mixture was stirred 1 h at 0° C., 1 h at 21° C., and thenquenched with water and neutralized using 1N HCl. The organic extractswere washed (H₂O, brine), dried (MgSO₄), filtered and concentrated.Purification by flash chromatography (eluting with ethanol/ethylacetate, 1:9) provided the title compound.

¹H NMR (400 MHz, acetone-d6): δ 8.78 (dd, 1H), 8.33 (dd, 1H), 7.76 (d,1H), 7.49 (q, 1H), 7.45 (d, 1H), 7.42 (d, 1H), 7.29 (t, 4H), 7.13 (d,1H), 4.78 (t, 1H), 3.6 (m, 2H), 3.16 (m, 3H), 2.92 (q, 1H), 1.31 (s,6H).

EXAMPLE 684-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-methyl-3-pyrdin-4-yl-butan-2-ol

To a solution of Example 66 (750 mg, 1.77 mmol) in THF (40 mL) at 0° C.was added methylmagnesium iodide (3M, THF, 12 mL, 35 mmol) dropwise. Thereaction mixture was stirred 3 h at 0° C., then quenched with asaturated ammonium chloride solution. The organic extracts were washed(H₂O, brine), dried (MgSO₄), filtered and concentrated. Purification byflash chromatography (eluting with hexane/ethyl acetate, 1:1) providedthe title compound.

¹H NMR (400 MHz, acetone-d6): δ 8.77 (dd, 1H), 8.39 (dd, 2H), 8.27 (dd,1H), 7.71 (d, 1H), 7.45 (q, 1H), 7.41 (d, 2H), 7.30 (d, 3H), 7.18 (t,1H), 7.08 (d, 1H), 3.73 (s, 1H), 3.51 (dd, 1H), 3.16 (m, 2H), 3.03 (dd,1H), 1.36 (d, 6H), 1.28 (s,3H), 1.19 (s, 3H).

EXAMPLE 694-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-methyl-3-(1-oxy-pyridin-4-yl)-butan-2-ol

Following the procedures described in Example 61, but substitutingExample 68 for Example 60, the title compound was obtained.

¹H NMR (400 MHz, acetone-d6): δ 8.82 (dd, 1H), 8.27 (dd, 1H), 7.96 (d,2H), 7.73 (dd, 1H), 7.51 (d, 1H), 7.44 (q, 1H), 7.38 (m, 2H), 7.31 (d,2H), 7.22 (t, 1H), 7.09 (d, 1H), 3.84 (s, 1H), 3.48 (d, 1H), 3.15 (m,3H), 1.36 (t, 9H), 1.18 (s, 3H).

EXAMPLE 703-(3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-pyridin-4-yl-butyric acidethyl ester

Following the procedures described in Example 60, Steps 1-3, butsubstituting methylmagnesium iodide for 4-chlorophenylmagnesium bromide,the title compound was obtained as a mixture of diastereoisomer.

¹H NMR (500 MHz, acetone-d₆): δ 8.83 (dd, 1H), 8.36 (dd, 2H), 8.26 (dd,1H), 7.72 (d, 1H), 7.42 (m, 4H), 7.31 (dd, 2H), 7.22 (t, 1H), 7.13 (d,1H), 4.21 (m, 3H), 3.95 (d, 1H), 3.58 (m, 1H), 3.12 (m, 1H), 1.48 (d,3H), 1.36 (d, 6H), 1.18 (t, 2H).

EXAMPLE 714-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-methyl-3-pyridin-4-yl-pentan-2-ol

Following the procedures described in Example 68, but substitutingExample 70 for Example 66, the title compound was obtained as a mixtureof diastereoisomers.

¹H NMR (400 MHz, acetone-d6): δ 8.83 (dd, 1H), 8.34 (dd, 2H), 8.27 (dd,1H), 7.79 (d, 1H), 7.49 (m, 2H), 7.42 (d, 1H), 7.38 (dd, 2H), 7.28 (dd,2H), 7.18 (d, 1H), 4.39 (s, 1H), 3.58 (m, 1H), 3.12 (m, 1H), 2.88 (d,1H), 1.35 (d, 6H), 1.21 (s, 3H), 1.05 (d, 3H), 0.9 (s, 3H).

EXAMPLE 724-(4-Chloro-phenyl)4-[3-(6-isopropyl-quinolin-8-yl)-phenyl]-2-methyl-3-pyridin-4-yl-butan-2-ol

Following the procedures described in Example 60, Steps 1-3, the titlecompound was obtained as a mixture of diastereoisomers.

Isomer A: ¹H NMR (400 MHz, acetone-d6): δ 8.81 (dd, 1H), 8.48 (d, 2H),8.31 (dd, 1H), 7.92 (s, 1H), 7.78 (s, 1H), 7.68 (s, 1H), 7.58 (d, 1H),7.52 (d, 1H), 7.48 (q, 1H), 7.41 (m, 6H), 7.18 (d, 1H), 4.92 (d, 1H),4.81 (d, 1H), 4.02 (m, 2H), 3.12 (m, 1H), 1.39 (d, 6H), 0.92 (t, 3H).

Isomer B: ¹H NMR (500 MHz, acetone-d₆): δ 8.81 (dd, 1H), 8.48 (d, 1H),8.42 (dd, 1H), 8.31 (m, 2H), 7.72 (d, 1H), 7.68 (d, 1H), 7.62 (d, 1H),7.52 (d, 2H), 7.43 (m, 3H), 7.35 (d, 2H), 7.21 (t, 1H), 7.15 (d, 1H),4.95 (d, 1H), 4.78 (d, 1H), 3.98 (m, 2H), 3.11 (m, 1H), 1.37 (d, 6H),0.95 (t, 3H).

EXAMPLE 734-(4-Chloro-phenyl)-4-[3-(6-isopropyl-quinolin-8-yl)-phenyl]-2-methyl-3-pyridin-4-yl-butan-2-ol

Following the procedures described in Example 68, but substitutingExample 72 for Example 66, the title compound was obtained as a mixtureof diastereoisomer.

¹H NMR (400 MHz, acetone-d6): δ 8.81 (dd, 1H), 8.48 (d, 2H), 8.31 (dd,1H), 7.92 (s, 1H), 7.78 (s, 1H), 7.68 (s, 1H), 7.58 (d, 1H), 7.52 (d,1H), 7.48 (q, 1H), 7.41 (m, 6H), 7.18 (d, 1H), 5.0 (d, 1H), 4.02 (d,1H), 3.15 (m, 1H), 1.38 (m 9H), 1.1 (t, 3H).

EXAMPLE 742-Pyridin-4-yl-3-[3-(6-pyridin-4-ylmethyl-quinolin-8-yl)-phenyl]-propionicacid ethyl ester

Using procedures described in Example 60, Step 3, but using3-bromobenzyl chloride as the starting material, followed by theprocedures described in Example 62, Step 2, but substituting 8-bromo6-[(4-pyridinyl)methyl]quinoline for 8-bromoquinoline, the titlecompound was obtained as a oil.

¹H NMR (500 MHz, acetone-d6): δ 8.82 (dd, 1H), 8.46 (q, 4H), 8.30 (dd,1H), 7.81 (s, 1H), 7.50 (s, 1H), 7.48 (m, 2H), 7.44 (s, 1H), 7.34 (m,5H), 7.22 (d, 1H), 4.25 (s, 2H), 4.05 (m, 3H), 3.44 (dd, 1H), 3.13 (dd,1H), 1.07 (t, 3H).

EXAMPLE 752-Methyl-3-pyridin-4-yl-4-[3-(6-pyridin-4-ylmethyl-quinolin-8-yl)-phenyl]-butan-2-ol

Following the procedures described in Example 68, but substitutingExample 74 for Example 66, the title compound was obtained.

¹H NMR (400 MHz, acetone-d6): δ 8.81 (dd, 1H), 8.48 (dd, 2H), 8.36 (dd,2H), 8.27 (dd, 1H), 7.76 (d, 1H), 7.48 (q, 1H), 7.34 (m, 5H), 7.28 (d,2H), 7.18 (t, 1H), 7.05 (d, 1H), 4.23 (s, 2H), 3.48 (dd, 1H), 3.11 (m,2H), 1.32 (s, 3H), 1.14 (s, 3H).

EXAMPLE 768-{3-[1-(4-Chloro-phenyl)-2-pyridin-4-yl-ethyl]-phenyl}-6-pyridin-4-ylmethyl-quinoline

Following the procedures described in Example 62, but substituting8-bromo-6-pyridin-4-ylmethyl-quinoline for 8-bromoquinoline andpurification by flash chromatography (eluting with ethyl acetate/EtOH,10:0 to 9:1) afforded the title compound.

¹H NMR (500 MHz, acetone-d6): δ 8.84 (dd, 1H), 8.48 (dd, 2H), 8.35 (dd,2H), 8.29 (dd, 1H), 7.81 (d, 1H), 7.68 (s, 1H), 7.51 (d, 1H), 7.45 (m,2H), 7.40 (d, 2H), 7.32 (dd, 4H), 7.27 (d, 2H), 7.20 (dd, 2H), 4.50 (t,1H), 4.24 (s, 2H), 3.47 (m, 2H).

EXAMPLE 773-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-pyridin-4-yl-propionitrile

Step 1: 3-(3-Bromo-phenyl)-2-pyridin-4-yl-propionitrile

The procedures described in Example 60, Step 3, were followed butsubstituting 4-pyridinylacetonitrile for ethyl 4-pyridinylacetate andusing 3-bromobenzyl chloride as the starting material.

Step 2:3-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-pyridin-4-yl-propionitrile

Following the procedures described in Example 62, Step 2, butsubstituting 8-bromo-6-isopropylquinoline for 8-bromoquinoline andpurification by flash chromatography (eluting with ethylacetate/hexane,75:25) afforded the3-[3-(6-isopropyl-quinolin-8-yl)-phenyl]-2-pyridin-4-yl-propionitrilecompound.

¹H NMR (500 MHz, acetone-d6): δ 8.81 (dd, 1H), 8.60 (dd, 2H), 8.30 (dd,1H), 7.76 (d, 1H), 7.65 (d, 1H), 7.60 (d, 1H); 7.54 (s, 1H), 7.47 (q,1H), 7.43 (dd, 2H), 7.39 (t, 1H), 7.29 (d, 1H), 4.56 (t, 1H), 3.36 (d,2H), 3.16 (m, 1H), 1.37 (s, 6H).

EXAMPLE 783-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-(4-methanesulfonyl-phenyl)-propionitrile

Step 1: (4-Methanesulfonyl-phenyl)-acetonitrile

To a solution of 4-methanesulfonylbenzyl chloride (10 g, 49 mmol) in DMF(100 mL) was added HMPA (9.35 mL, 54 mmol) and KCN (3.5 g, 54 mmol). Theresulting reaction mixture was stirred 18 h at 80° C., then diluted withwater and ethyl acetate. The organic extracts were washed (NaHCO₃,brine), dried (MgSO₄), filtered and concentrated. Purification by flashchromatography (eluting with hexane/ethyl acetate, 1:1 to 25:75)provided the (4-methanesulfonyl-phenyl)-acetonitrile compound.

Step 2:3-[3-(6-Isopropylquinolin-8-yl)-phenyl]-2-[4-(methylsulfonyl)-phenyl]-prop-2-enenitrile

A solution of Quinoline 04 (5 g, 18 mmol), 4-methanesulfonylacetonitrile(3.5 g, 18 mmol) from Step 1 and piperidine (0.1 mL) in toluene (5 mL)was heated at 130° C. After 6 h, the mixture was cooled to 21° C. andpurified by flash chromatography (eluting with ethylacetate/hexane, 1:1to 75:25) to afforded the title compound.

Step 3:3-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-(4-methanesulfonyl-phenyl)-propionitrile

A solution of the nitrile from Step 2 (400 mg, 0.88 mmol) in THF/EtOH(1:1, 10 mL) containing Pd/C (10%, 40 mg) was stirred under H₂ (1 atm)for 3 days. Filtration on celite, evaporation, stirring vigorously inether for 1 h then filtration afforded the3-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-(4-methanesulfonyl-phenyl)-propionitrilecompound as a white powder.

¹H NMR (500 MHz, acetone-d₆): δ 8.81 (dd, 1H), 8.31 (dd, 1H), 7.97 (d,2H), 7.78 (s, 1H), 7.76 (d, 2H), 7.68 (s, 1H), 7.64 (d, 2H), 7.46 (q,1H), 7.40 (t, 1H), 7.29 (d, 1H), 4.68 (t, 1H), 3.42 (dd, 2H), 3.15 (m,1H), 3.08 (s, 3H), 1.38 (s, 6H).

EXAMPLE 796-Isopropyl-8-{3-[2-(4-methanesulfonyl-phenyl)-2-(1H-tetrazol-5-yl)-ethyl]-phenyl}-quinoline

A solution of Example 78 (160 mg, 0.35 mmol), tri-n-butyltin chloride(0.478 mL, 1.76 mmol) and sodium azide (115 mg, 1.76 mmol) in xylene (5mL) was heated at 150° C. for 18 h. Cooling to 21° C., then purificationby flash chromatography (eluting with CH₂Cl₂/MeOH, NH₄OH, 50:5:1)followed by stirring vigorously in ether for 1 h, then filtered,afforded the title compound as a white powder.

¹H NMR (500 MH, acetone-d₆): δ 8.88 (d, 1H), 8.42 (d, 1H), 7.91 (d, 2H),7.83 (s, 1H), 7.81 (d, 2H), 7.64 (dd, 2H), 7.56 (q, 1H), 7.49 (d, 1H),7.29 (t, 1H), 7.12 (d, 1H), 5.13 (q, 1H), 3.68 (q, 1H), 3.54 (q, 1H),3.21 (m, 1H), 3.06 (s, 3H), 1.38 (d, 6H).

EXAMPLE 803-{3-[6-(Cyano-dimethyl-methyl)-quinolin-8-yl]-phenyl}-N-isopropyl-2-(4-methanesulfonyl-phenyl)-propionamide

Step 1: (E)-3-(3-Bromophenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenoicacid

To a solution of 3-bromobenzaldehyde (12.9 g, 70 mmol) in toluene (100mL) was added 4-(methylsulfonyl)phenylacetic acid (15 g, 70 mmol) andpiperidine (2 mL). After overnight refluxing, the mixture was cooleddown to r.t. To the slurry thus formed, toluene was added (10 mL).Filtration gave the(E)-3-(3-bromophenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenoic acid as awhite solid.

Step 2:(E)-N-Isopropyl-3-(3-bromophenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenamide

To a solution of(E)-3-(3-bromophenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenoic acid fromStep 1 (24.9 g, 65 mmol) in toluene (250 mL) was added thionyl chloride(14.3 mL, 196 mmol) and triethylamine (34 mL, 245 mmol). After stirringat 21° C. for 0.5 h., isopropyl amine (28 mL, 327 mmol) was added. Aftera further 2 h at r.t., the mixture was cooled to 0° C. and wasneutralised with saturated NH₄Cl solution, then extracted with EtOAc.The organic extracts were washed (H₂O, brine), dried (MgSO₄), filteredand concentrated. Purification by flash chromatography (Hex:EtOAc, 1:1to pure EtOAc) yielded the(E)-N-isopropyl-3-(3-bromophenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenamidecompound.

Step 3:3-{3-[6-(Cyano-dimethyl-methyl)-quinolin-8-yl]-phenyl}-N-isopropyl-2-(4-methanesulfonyl-phenyl)-acrylamide

Following the procedures described above in Example 62, Step 2, butsubstituting Quinoline 08 for 8-bromoquinoline and purification by flashchromatography (eluting with ethylacete/hexane, 75:25) afforded the3-{3-[6-(Cyano-dimethyl-methyl)-quinolin-8-yl]-phenyl}-N-isopropyl-2-(4-methanesulfonyl-phenyl)-acrylamidecompound.

Step 4:3-{3-[6-(Cyano-dimethyl-methyl)-quinolin-8-yl]-phenyl}-N-isopropyl-2-(4-methanesulfonyl-phenyl)-propionamide

A solution of3-{3-[6-(cyano-dimethyl-methyl)-quinolin-8-yl]-phenyl}-N-isopropyl-2-(4-methanesulfonyl-phenyl)-acrylamidefrom Step 3 (20 mg, 0.038 mmol) in THF (1 mL) containing Pd/C (10%, 9mg) was stirred under H₂ (50 psi) for 18 h. Filtration on celite,evaporation, and purification on HPLC (u-porasil ethyl acetate/hexane,70:30 to 100:0, over 30 min.) afforded the3-{3-[6-(cyano-dimethyl-methyl)-quinolin-8-yl]-phenyl}-N-isopropyl-2-(4-methanesulfonyl-phenyl)-propionamidecompound as a foam.

Example 80 can also be prepared according to the procedure described inExample 1 but using Quinoline 09 and Ester 05 as the starting material.After flash chromatography (hexane/EtOAc 50:50), the residue was stirredvigorously in ether for 1 h then filtered to afford the3-{(3-[6-(cyano-dimethyl-methyl)-quinolin-8-yl]-phenyl}-N-isopropyl-2-(4-methanesulfonyl-phenyl)-propionamidecompound as a white powder.

¹H NMR (500 MHz, acetone-d₆): δ 8.92 (dd, 1H), 8.46 (d, 1H), 8.11 (d,1H), 7.86 (d, 3H), 7.72 (d, 2H), 7.65 (s, 1H), 7.58 (q, 1H), 7.51 (d,1H), 7.35 (t, 1H), 7.28 (d, 1H), 7.12 (d, 1H), 3.96 (t, 1H), 3.85 (m,1H), 3.51 (t, 1H), 3.07 (m, 4H), 1.85 (s, 6H), 0.93 (d, 3H), 0.88 (d,3H).

EXAMPLE 816-(1-Methanesulfonyl-1-methyl-ethyl)-8-{3-[2-(4-methanesulfonyl-phenyl)-2-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-phenyl}-quinoline

Example 81 was prepared according to the procedure described above inExample 1 but using Quinoline 01 and Ester 06 as the starting materialand the reaction performed from −78° C. to 21° C. Flash chromatography(hexane/EtOAc 50:50 to 10:90) afforded the title compound.

¹H NMR (500 MHz, acetone-d₆): δ 8.91 (dd, 1H), 8.43 (dd, 1H), 8.24 (d,1H), 8.01 (d, 1H), 7.90 (d, 2H), 7.74 (d, 2H), 7.60 (s, 1H), 7.54 (m,2H), 7.33 (t, 1H), 7.25 (d, 1H), 4.97 (t, 1H), 3.73 (q, 1H), 3.48 (q,1H), 3.06 (s, 3H), 2.70 (s, 3H), 2.31 (s, 3H), 1.96 (d, 6H).

EXAMPLE 823-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-(4-methanesulfonyl-phenyl)-propionicacid methyl ester

Step 1:3-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-(4-methylsulfanyl-phenyl)-propionicacid methyl ester

Following the procedures described in Example 13, Step 1, butsubstituting Quinoline 06 for Quinoline 01, the3-[3-(6-isopropyl-quinolin-8-yl)-phenyl]-2-(4-methylsulfanyl-phenyl)-propionicacid methyl ester compound was obtained as a white foam.

Step 2:3-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-(4-methanesulfonyl-phenyl)-propionicacid methyl ester

A solution of3-[3-(6-isopropyl-quinolin-8-yl)-phenyl]-2-(4-methylsulfanyl-phenyl)-propionicacid methyl ester from Step 1 (1.05 g, 2.3 mmol), NMO (655 mg, 4.85mmol) and OsO₄ (4%, H₂O, 1 mL, 0.16 mmol) in THF (20 mL) was stirred 18h at 21° C. The resulting reaction mixture was diluted with a sodiummetabisulfite solution and ethyl acetate. The organic extracts werewashed (H₂O, brine), dried (MgSO₄), filtered and concentrated.Purification by flash chromatography (eluting with hexane/ethyl acetate,80:20) provided the3-[3-(6-isopropyl-quinolin-8-yl)-phenyl]-2-(4-methanesulfonyl-phenyl)-propionicacid methyl ester compound.

¹H NMR (400 MHz, acetone-d6): δ 8.81 (dd, 1H), 8.29 (dd, 1H), 7.89 (dd,2H), 7.76 (d, 1H), 7.67 (d, 2H), 7.63 (d, 1H), 7.56-7.53 (m, 2H), 7.46(dd, 1H), 7.32 (t, 1H), 7.21 (d, 1H), 4.23 (t, 1H), 3.61 (s, 3H), 3.54(dd, 1H), 3.19-3.13 (m, 2H), 3.06 (s, 3H), 1.37 (s, 3H), 1.36 (s, 3H).LRMS (CI) 488 (M+H)⁺.

EXAMPLE 833-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-(4-methanesulfonyl-phenyl)-propionicacid

Following the procedures described in Example 8, but substitutingExample 82 for Example 7, the title compound was obtained as a whitesolid.

¹H NMR (400 MHz, acetone-d6): δ 8.81 (dd, 1H), 8.29 (dd, 1H), 7.98 (d,2H), 7.76 (s, 1H), 7.70 (d, 2H), 7.64 (dd, 1H), 7.59 (s, 1H), 7.54 (d,1H), 7.47 (dd, 1H), 7.32 (t, 1H), 7.24 (d, 1H), 4.22 (t, 1H), 3.53 (dd,1H), 3.20-3.13 (m, 2H), 3.07 (s, 3H), 1.38 (s, 3H), 1.36 (s, 3H). LRMS(CI) 474 (M+H)⁺430 (M+H−COOH)⁺.

EXAMPLE 846-Isopropyl-8-{3-[2-(4-methanesulfonyl-phenyl)-2-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-phenyl}-quinoline

To a solution of Example 83 (177 mg, 0.37 mmol) in diglyme (3 mL) wasadded EDCI (93 mg, 0.48 mmol) and, after 10 min, N-hydroxyacetamidine(41 mg, 0.55 mmol). The resulting reaction mixture was stirred 3 h at110° C., then diluted with a saturated sodium bicarbonate solution andethyl acetate. The organic extracts were washed (H₂O, brine), dried(MgSO₄), filtered and concentrated. Purification by flash chromatography(eluting with hexane/ethyl acetate, 80:20 to 100:0) provided the titlecompound.

¹H NMR (400 MHz, acetone-d6): δ 8.81 (dd, 1H), 8.30 (dd, 1H), 7.91 (dd,2H), 7.77-7.74 (m, 3H), 7.59 (d, 1H), 7.56-7.53 (m, 2H), 7.47 (dd, 1H),7.31 (t, 1H), 7.22 (d, 1H), 4.97 (t, 1H), 4.74 (dd, 1H), 3.48 (dd, 1H),3.16 (q, 1H), 3.06 (s, 3H), 2.32 (s, 3H), 1.38 (s, 3H), 1.37 (s, 3H).LRMS (CI) 512 (M+H)⁺.

EXAMPLE 853-(2-Cyano-phenyl)-2-[3-(6-isopropyl-quinolin-8-yl)-phenyl]-propionicacid methyl ester

To a solution of Quinoline 05 (100 mg, 0.31 mmol) in THF/DMF (1:1, 3 mL)at −78° C. was added potassium tert-butoxide (1M, 0.31 mL, 0.31 mmol)dropwise. The resulting reaction mixture was stirred 5 min., thencannulated into a solution of 2-cyanobenzylbromide (123 mg, 0.63 mmol)in THF (1 mL) at 21° C. After 3 h, the reaction mixture was diluted witha saturated ammonium chloride solution and ethyl acetate. The organicextracts were washed (H₂O, brine), dried (MgSO₄), filtered andconcentrated. Purification by flash chromatography (eluting withhexane/ethyl acetate, 80:20 to 20:80) provided the title compound.

¹H NMR (300 MHz, acetone-d6): δ 8.81 (dd, 1H), 8.28 (dd, 1H), 7.50 (s,11H), 4.19 (t, 1H), 3.65 (dd, 1H), 3.61 (s, 3H), 3.39 (dd, 1H), 3.15 (m,1H), 1.37 (d, 6H).

EXAMPLE 863-(3-Cyano-phenyl)-2-[3-(6-isopropyl-quinolin-8-yl)-phenyl]-propionicacid methyl ester

Following the procedures described above in Example 85, but substituting3-cyanobenzylbromide for 2-cyanobenzylbromide, the title compound wasobtained.

¹H NMR (300 MHz, acetone-d6): δ 8.83 (dd, 1H), 8.29 (dd, 1H), 7.76 (d,1H), 7.68 (s, 2H), 7.65-7.30 (m, 8H), 4.10 (t, 1H), 3.60 (s, 3H), 3.49(dd, 1H), 3.20 (dd, 1H), 3.15 (m, 1H), 1.39 (d, 6H).

EXAMPLE 873-(4-Cyano-phenyl)-2-[3-(6-isopropyl-quinolin-8-yl)-phenyl]-propionicacid methyl ester

Following the procedures described above in Example 85, but substituting4-cyanobenzylbromide for 2-cyanobenzylbromide, the title compound wasobtained.

¹H NMR (300 MHz, acetone-d6): δ 8.82 (dd, 1H), 8.30 (dd, 1H), 7.80 (d,1H), 7.70-7.30 (m, 10H), 4.10 (t, 1H), 3.61 (s, 3H), 3.52 (dd, 1H), 3.25(dd, 1H), 3.18 (m, 1H), 1.38 (d, 6H).

EXAMPLE 883-(2-Chloro-4-fluoro-phenyl)-2-[3-(6-isopropyl-quinolin-8-yl)-phenyl]-propionicacid methyl ester

Following the procedures described above in Example 85, but substituting2-chloro-4-fluorobenzyl bromide for 2-cyanobenzylbromide, the titlecompound was obtained.

¹H NMR (300 MHz, acetone-d6): δ 8.83 (dd, 1H), 8.28 (dd, 1H), 7.77-7.30(m, 9H), 6.98 (dt, 1H), 4.13 (t, 1H), 3.61 (s, 3H), 3.53 (dd, 1H), 3.25(dd, 1H), 3.17 (m, 1H), 1.38 (d, 6H).

EXAMPLE 892-[3-(6-isopropylquinolin-8-yl)-phenyl]-3-[4-(1,2,3-thiadiazol-5-yl)-phenyl]-propionicacid methyl ester

Following the procedures described above in Example 85, but substituting4-(4-bromomethylphenyl)-[1,2,3]thiadiazole for 2-cyanobenzylbromide, thetitle compound was obtained.

¹H NMR (400 MHz, acetone-d6): δ 9.29 (s, 1H), 8.82 (dd, 1H), 8.30 (dd,1H), 8.06 (d, 2H), 7.76 (d, 1H), 7.65-7.59 (m, 3H), 7.49-7.23 (m, 5H),4.11 (t, 1H), 3.61 (s, 3H), 3.52 (dd, 1H), 3.22 (dd, 1H), 3.09 (m, 1H),1.31 (d, 6H).

EXAMPLE 902-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-3-pyridin-4-yl-propionic acidmethyl ester

Following the procedures described above in Example 85, but substituting4-picolyl chloride for 2-cyanobenzylbromide, the title compound wasobtained.

¹H NMR (300 MHz, acetone-d6): δ 8.82 (dd, 1H), 8.45 (d, 2H), 8.30 (dd,1H), 7.80 (d, 1H), 7.70-7.35 (m, 6H), 7.25 (d, 2H), 4.15 (t, 1H), 3.60(s, 3H), 3.46 (dd, 1H), 3.18 (m, 2H), 1.39 (d, 6H).

EXAMPLE 91 2-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-3-phenyl-propionicacid methyl ester

Following the procedures described above in Example 85, but substitutingbenzyl chloride for 2-cyanobenzylbromide, the title compound wasobtained.

¹H NMR (300 MHz, acetone-d6): δ 8.81 (dd, 1H), 8.30 (dd, 1H), 7.77 (d,1H), 7.70-7.10 (m, 11H), 4.05 (t, 1H), 3.60 (s, 3H), 3.45 (dd, 1H), 3.18(m, 1H), 3.12 (dd, 1H), 1.40 (d, 6H).

EXAMPLE 922-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-3-(4-methanesulfonyl-phenyl)-propionicacid methyl ester

Following the procedures described above in Example 85, but substituting4-methanesulfonylbenzyl chloride for 2-cyanobenzylbromide, the titlecompound was obtained.

¹H NMR (400 MHz, acetone-d6): □8.85 (dd, 1H), 8.32 (dd, 1H), 7.81 (m,3H), 7.72 (s, 1H), 7.69 (s, 1H), 7.61 (d, 1H), 7.56 (d, 2H), 7.49 (dd,1H), 7.40 (t, 1H), 7.34 (d, 1H), 4.12 (t, 1H), 3.60 (s, 3H), 3.55 (dd,1H), 3.38 (dd, 1H), 3.29 (m, 1H), 3.05 (s, 3H), 1.38 (d, 6H).

EXAMPLE 932-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-3-(4-methanesulfonyl-phenyl)-propionicacid

Following the procedures described above in Example 8, but substitutingExample 92 for Example 7, the title compound was obtained.

¹H NMR (400 MHz, acetone-d6): δ 8.85 (dd, 1H), 8.31 (dd, 1H), 7.82 (d,2H), 7.78 (d, 2H), 7.68 (s, 1H), 7.60 (m, 3H), 7.48 (dd, 1H), 7.40 (m,2H), 4.10 (t, 1H), 3.55 (dd, 1H), 3.25 (dd, 1H), 3.18 (m, 1H), 3.05 (s,3H), 1.38 (s, 6H).

EXAMPLE 943-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]4-(4-methanesulfonyl-phenyl)-2-methyl-butan-2-ol

To a solution of Example 92 (100 mg, 0.2 mmol) in CH₂Cl₂ (2 mL) at −78°C. was added methylmagnesium chloride (3M, THF, 0.2 mL, 0.6 mmol)dropwise. The resulting reaction mixture was stirred 1 h at 21° C., thenquenched with a saturated ammonium chloride solution. The organicextracts were washed (H₂O, brine), dried (MgSO₄), filtered andconcentrated. Purification by flash chromatography (eluting withhexane/ethyl acetate, 7:3) provided the title compound.

¹H NMR (300 MHz, acetone-d6): δ 8.85 (dd, 1H), 8.30 (dd, 1H), 7.80-7.65(m, 5H), 7.55-7.45 (m, 4H), 7.35-7.20 (m, 2H), 3.70 (brs, 1H), 3.60 (dd,1H), 3.30 (t, 1H), 3.15 (dd, 1H), 3.12 (m, 1H), 3.00 (s, 3H), 1.38 (d,6H), 1.30 (s, 3H), 1.25 (s, 3H).

EXAMPLE 95N-Isopropyl-2-[3-(6-isopropyl-quinolin-8-yl)-phenyl]-3-(4-methanesulfonyl-phenyl)-propionamide

To a solution of Example 93 (100 mg, 0.21 mmol) in CH₂Cl₂ (2 mL) wasadded DMAP (26 mg, 0.21 mmol), EDCI (45 mg, 0.23 mmol), then isopropylamine (1 mL, 12 mmol). The resulting reaction mixture was stirred 18 hat 21° C., then diluted with a sodium bicarbonate solution and ethylacetate. The organic extracts were washed (H₂O, brine), dried (MgSO₄),filtered and concentrated. Purification by flash chromatography (elutingwith hexane/ethyl acetate, 80:20 to 20:80) provided the title compound.

¹H NMR (300 MHz, acetone-d6): δ 8.82 (dd, 1H), 8.35 (dd, 1H), 7.95 (m,1H), 7.85-7.75 (m, 4H), 7.65-7.52 (m, 3H), 7.50 (dd, 1H), 7.45-7.35 (m,2H), 7.10 (brd, 1H), 3.88 (m, 2H), 3.59 (dd, 1H), 3.15 (m, 2H), 3.09 (s,3H), 1.38 (d, 6H), 0.99 (d, 3H), 0.96 (d, 3H).

EXAMPLE 966-Isopropyl-8-{3-[2-(4-methanesulfonyl-phenyl)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-phenyl}-quinoline

Following the procedures described above in Example 84, but substitutingExample 93 for Example 83, the title compound was obtained.

¹H NMR (300 MHz, acetone-d6): δ 8.82 (dd, 1H), 8.30 (dd, 1H), 7.80 (m,4H), 7.70-7.58 (m, 4H), 7.50 (dd, 1H), 7.40 (m, 2H), 4.85 (t, 1H), 3.78(dd, 1H), 3.60 (dd, 1H), 3.28 (m, 1H), 3.05 (s, 3H), 2.30 (s, 3H), 1.40(d, 6H).

EXAMPLE 972-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-3-(4-methanesulfonyl-phenyl)-propionitrile

Following the procedures described above in Example 85, but substitutingQuinoline 07 for Quinoline 05 and substituting 4-methanesulfonylbenzylchloride for 2-cyanobenzylbromide, the title compound was obtained.

¹H NMR (300 MHz, acetone-d6): δ 8.85 (dd, 1H), 8.30 (dd, 1H), 7.90 (d,2H), 7.80 (m, 2H), 7.70 (m, 2H), 7.60 (d, 2H), 7.45 (m, 3H), 4.57 (t,1H), 3.45 (d, 2H), 3.19 (m, 1H), 3.09 (s, 3H), 1.40 (d, 6H).

EXAMPLE 982-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-3-pyridin-3-yl-propionic acidmethyl ester

Following the procedures described above in Example 85, but substituting3-picolyl chloride for 2-cyanobenzylbromide, the title compound wasobtained.

¹H NMR (400 MHz, acetone-d6): δ 8.82 (dd, 1H), 8.48 (d, 1H), 8.38 (dd,1H), 8.29 (dd, 1H), 7.77 (d, 1H), 7.68 (t, 1H), 7.64 (m, 3H), 7.47 (dd,1H), 7.41 (t, 1H), 7.34 (d, 1H), 7.22 (dd, 1H), 4.06 (t, 1H), 3.59 (s,3H), 3.42 (dd, 1H), 3.16 (m, 2H), 1.37 (d, 6H).

EXAMPLE 992-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-3-(4-methanesulfonyl-phenyl)-2-methyl-propionicacid methyl ester

To a solution of Example 92 (90 mg, 0.185 mmol) in THF/DMF (1:1, 2 mL)at −78° C. was added potassium tert-butoxide (1M, 0.19 mL, 0.19 mmol)dropwise followed by MeI (0,014 mL, 0.22 mmol) after 15 min. Theresulting reaction mixture was stirred 18 h at 21° C., then diluted witha saturated ammonium chloride solution and ethyl acetate. The organicextracts were washed (H₂O, brine), dried (MgSO₄), filtered andconcentrated. Purification by flash chromatography (eluting withhexane/ethyl acetate, 50:50) provided the title compound.

¹H NMR (300 MHz, acetone-d6): δ 8.84 (dd, 1H), 8.30 (dd, 1H), 7.80-7.70(m, 5H), 7.62 (d, 1H), 7.49 (dd, 1H), 7.40 (m, 3H), 7.30 (d, 1H), 3.70(s, 3H), 3.52 (dd, 2H), 3.20 (m, 1H), 3.03 (s, 3H), 1.55 (s, 3H), 1.40(d, 6H).

EXAMPLE 1002-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-(4-methanesulfonyl-phenyl)-cyclopropanecarboxylicacid

Step 1:3-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-acrylicacid

Following the procedures described above in Example 80, Step 1, butsubstituting Quinoline 03 for 3-bromobenzaldehyde, the3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-acrylicacid compound was obtained as a white solid.

Step 2:3-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-acrylicacid methyl ester

Following the procedures described above in Ester 01, the3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-acrylicacid methyl ester compound was obtained as a white solid.

Step 3:2-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-(4-methanesulfonyl-phenyl)-cyclopropanecarboxylicacid methyl ester

To a suspension of trimethylsulfoxonium iodide (400 mg, 1.83 mmol) inDMSO (25 mL) at 0° C. was added NaH (60%, 73 mg, 1.83 mmol). After 30min.,3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-acrylicacid methyl ester from Step 2 (688 mg, 1.22 mmol) was added and theresulting reaction mixture stirred for 18 h at 21° C., then diluted withwater and ethyl acetate. The organic extracts were washed (H₂O, brine),dried (MgSO₄), filtered and concentrated. Purification by flashchromatography (eluting with toluene/acetone, 80:20) provided the2-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-(4-methanesulfonyl-phenyl)-cyclopropanecarboxylicacid methyl ester compound.

Step 4:2-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-(4-methanesulfonyl-phenyl)-cyclopropanecarboxylicacid

Following the procedures described above in Example 08, the2-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)quinolin-8-yl]-phenyl}-1-(4-methanesulfonyl-phenyl)-cyclopropanecarboxylicacid compound was obtained as a white solid.

¹H NMR (400 MHz, acetone-d6): δ 8.91 (dd, 1H), 8.44 (dd, 1H), 8.26 (d,1H), 8.13 (d, 1H), 7.92 (d, 2H), 7.85 (d, 2H), 7.80 (s, 1H), 7.66 (d,1H), 7.55 (dd, 1H), 7.52 (d, 1H), 7.45 (m, 1H), 3.12 (s, 3H), 3.06 (t,1H), 2.73 (s, 3H), 2.42 (dd, 1H), 1.98 (s, 6H), 1.74 (dd, 1H).

EXAMPLE 101[2-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-(4-methanesulfonyl-phenyl)-cyclopropyl]-methanol

Using the compound from Example 100, Step 3 as the starting material andfollowing the procedures described above in Example 15 and purificationby flash chromatography (eluting with CH₂Cl₂/ethyl acetate, 60:40)provided the title compound.

¹H NMR (300 MHz, acetone-d6): δ 8.86 (dd, 1H), 8.45 (dd, 1H), 8.28 (d,1H), 8.20 (d, 1H), 7.91 (brs, 1H), 7.87 (d, 2H), 7.80 (d, 2H), 7.55 (m,2H), 7.48 (m, 2H), 3.95 (dd, 1H), 3.75 (dd, 1H), 3.55 (dd, 1H), 3.09 (s,3H), 2.75 (m, 1H), 2.71 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H), 1.58 (dd,1H), 1.46 (dd, 1H).

EXAMPLE 1022-[2-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-(4-methanesulfonyl-phenyl)-cyclopropyl]-propan-2-ol

Using the compound from Example 100, Step 3 as the starting material andfollowing the procedures described above in Example 29 and purificationby flash chromatography (eluting with CH₂Cl₂/ethyl acetate, 60:40)provided the title compound.

¹H NMR (300 MHz, acetone-d6): δ 8.90 (dd, 1H), 8.45 (dd, 1H), 8.28 (d,1H), 8.19 (d, 1H), 7.99 (s, 1H), 7.87 (s, 4H), 7.56 (m, 3H), 7.47 (t,1H), 3.10 (s, 3H), 2.72 (s, 3H), 2.55 (t, 1H), 2.04 (m, 1H), 2.00 (s,3H), 1.99 (s, 3H), 1.32 (dd, 1H), 1.17 (s, 3H), 1.06 (s, 3H).

EXAMPLE 1038-{4-Fluoro-3-[2-(4-methanesulfonyl-phenyl)ethyl]-phenyl}-6-isopropyl-quinoline

Step 1: 4-Fluoro-3-hydroxymethyl-benzene-boronic acid

To a solution of 4-bromo-2-fluoro-benzyl alcohol (10 g, 49 mmol) in TBF(500 mL) at −78° C. was added BuLi (2.5M, 43 mL, 107 mmol) dropwisekeeping the internal temperature below −73° C. After 25 min.,trimethylborate (25 mL, 107 mmol) was added and the resulting reactionmixture stirred for 15 h at −78° C., 1 h at 21° C., then diluted withHCl 10% and ethyl acetate. The organic extracts were washed (H₂O,brine), dried (MgSO₄), filtered and concentrated. The residue wassolidified from hexane/ethyl acetate with water (5 drops) to afford the4-fluoro-3-hydroxymethyl-benzene-boronic acid compound as a white solid.

Step 2: [2-Fluoro-5-(6-isopropyl-quinolin-8-yl)-phenyl]-methanol

Following the procedures described above in Quinoline 01, Step 3, andpurification by flash chromatography (eluting with hexane/ethyl acetate,70:30) provided the[2-fluoro-5-(6-isopropyl-quinolin-8-yl)-phenyl]-methanol compound.

Step 3: 2-Fluoro-5-(6-isopropyl-quinolin-8-yl)-benzaldehyde

A solution of [2-fluoro-5-(6-isopropyl-quinolin-8-yl)-phenyl]-methanolfrom Step 2 (2.23 g, 7.55 mmol) and MnO₂ (13 g, 150 mmol) in CH₂Cl₂ (70mL) was stirred at 21° C. for 18 h. The mixture was filtered through apad of celite and concentrated. Purification by flash chromatography(eluting with hexane/ethyl acetate, 70:30) provided the2-fluoro-5-(6-isopropylquinolin-8-yl)-benzaldehyde compound.

Step 4:8-{4-Fluoro-3-[2-(4-methanesulfonyl-phenyl)-vinyl]-phenyl}-6-isopropyl-quinoline

A solution of 4-methanesulfonylbenzyl chloride (10 g, 49 mmol) andtriphenylphosphine (12.8 g, 49 mmol) in acetonitrile (100 mL) wasstirred for 18 h at reflux. The resulting reaction mixture was cooled to21° C. and the phosphorus salt crystallised from CH₃CN/ether. To asuspension of the salt (875 mg, 1.87 mmol) in THF (15 mL) at 0° C. wasadded potassium tert-butoxide (1M, THF, 1.87 mL, 1.87 mmol) dropwise andthe resulting mixture stirred 30 min at 0° C. The mixture was cooled to−78° C. and the 2-fluoro-5-(6-isopropyl-quinolin-8-yl)-benzaldehyde fromStep 3 (0.5 g, 1.7 mmol, in THF) was added. After 90 min. at 21° C., thereaction mixture was diluted with HCl 10% and ethyl acetate. The organicextracts were washed (H₂O, brine), dried (MgSO₄), filtered andconcentrated. Purification by flash chromatography (eluting withhexane/ethyl acetate, 60:40) provided the8-{4-fluoro-3-[2-(4-methanesulfonyl-phenyl)-vinyl]-phenyl}-6-isopropyl-quinolinecompound as a mixture of isomer (3:1).

Step 5:8-{4-Fluoro-3-[2-(4-methanesulfonyl-phenyl)-ethyl]-phenyl}-6-isopropyl-quinoline

A solution of8-{4-fluoro-3-[2-(4-methanesulfonyl-phenyl)-vinyl]-phenyl}-6-isopropyl-quinolinefrom Step 4 (200 mg, 0.45 mmol) and polymer supported phenylsulfonylhydrazide (1.0 g) in toluene (10 mL) was heated at 100° C. for 18 h. Theresulting mixture was cooled at 21° C., filtered and the solventevaporated. Purification by flash chromatography (eluting withhexane/ethyl acetate, 70:30 to 40:60) provided the8-{4-fluoro-3-[2-(4-methanesulfonyl-phenyl)-ethyl]-phenyl}-6-isopropyl-quinolinecompound.

¹H NMR (300 MHz, acetone-d6): δ 8.82 (dd, 1H), 8.30 (dd, 1H), 7.87 (d,2H), 7.78 (dd, 1H), 7.70-7.59 (m, 3H), 7.55 (d, 2H), 7.45 (dd, 1H), 7.17(dd, 1H), 3.15 (m, 1H), 3.10 (brs, 4H), 3.05 (s, 3H), 1.40 (d, 6H).

EXAMPLE 1048-{2-Fluoro-5-[2-(4-methanesulfonyl-phenyl)-ethyl]-phenyl}-6-isopropyl-quinoline

Following the procedures described above in Example 103, butsubstituting 3-bromo-4-fluorobenzyl alcohol for 4-bromo-2-fluoro-benzylalcohol, the title compound was obtained.

¹H NMR (300 MHz, acetone-d6): δ 8.78 (dd, 1H), 8.30 (dd, 1H), 7.83 (d,2H), 7.81 (d, 1H), 7.63 (d, 1H), 7.51 (d, 2H), 7.45 (dd, 1H), 7.32 (m,2H), 7.10 (dd, 1H), 3.15 (m, 1H), 3.10 (m, 4H), 3.04 (s, 3H), 1.37 (d,6H).

EXAMPLE 1058-{3-[2-Cyclopropanesulfonyl-2-fluoro-2-(4-methanesulfonyl-phenyl)-ethyl]-phenyl}-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline

Following the procedures described above in Example 1, but substitutingSulfone 03 for Ketone 02 and then using the procedures described inExample 37 (2 steps in a one pot reaction) followed by purification byflash chromatography (eluting with ethyl acetate/hexane) afforded thetitle compound as a pale beige powder. The enantiomers can be separatedon a chiral column (ChiralPaK AD, hexane/EtOH/i-PrOH/MeOH, 30:30:30:10,retention time 8.1 and 10.2 min) to give Examples 105A and Example 105B.

¹H NMR (400 MHz, ace-d6): δ 8.88 (dd, 1H), 8.42 (dd, 1H), 8.23 (d, 1H),8.01-7.94 (m, 5H), 7.57-7.53 (s, 3H), 7.30 (t, 1H), 7.24 (d, 1H),4.05-3.97 (m, 2H), 3.08 (s, 3H), 2.70 (s, 3H), 2.49-2.43 (m, 1H), 1.97(s, 3H), 1.96 (s, 3H), 1.18-1.08 (m, 2H), 1.00-0.93 (m, 1H), 0.84-0.77(m, 1H).

EXAMPLE 1062-(4-Cyclopropanesulfonyl-phenyl)-4-hydroxy-1-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-4-methyl-pentan-3-one

Example 106 was prepared by following the procedures described above inExample 1, but substituting Sulfone 09 for Ketone 02. Purification byflash chromatography (eluting with ethyl acetate/hexane, 1:1 to 8:2)afforded the title compound.

¹H NMR (400 MHz, ace-d6): δ 8.93 (dd, 1H), 8.44 (dd, 1H), 8.26 (d, 1H),8.05 (d, 1H), 7.83 (d, 2H), 7.67 (d, 2H), 7.58-7.54 (m, 2H), 7.51 (appd, 1H), 7.33 (t, 1H), 7.22 (app d, 1H), 5.18 (d, 1H), 4.48 (s, 1H), 3.45(dd, 1H), 3.07 (dd, 1H), 2.71 (s, 3H), 2.60 (m, 1H), 1.95 (s, 6H), 1.14(dd, 2H), 1.10 (s, 3H), 1.05 (s, 3H), 1.00 (m, 2H).

EXAMPLE 1074-Ethyl-4-hydroxy-1-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-hexan-3-one

Example 107 was prepared by following the procedures described above inExample 1, but substituting Ketone 12 for Ketone 02. Purification byflash chromatography (eluting with ethyl acetate/hexane, 3:2) affordedthe title compound as a white foam.

¹H NMR (400 MHz, acetone-d6): δ 9.93 (dd, 1H), 8.44 (dd, 1H), 8.25 (d,1H), 8.03 (d, 1H), 7.85 (m, 2H), 7.67 (m, 2H), 7.57 (m, 2H), 7.48 (dd,1H), 7.32 (t, 1H), 7.20 (dd, 1H), 5.13 (t, 1H), 4.15 (s, OH), 3.42 (dd,1H), 3.09 (dd, 1H), 3.03 (s, 3H), 2.72 (s, 3H), 1.98 (s, 6H), 1.6-1.4(m, 4H), 0.49 (t, 6H).

EXAMPLE 1088-{3-[2,2-Bis-(4-chloro-phenyl)-cyclopropyl]-phenyl}-6-isopropyl-quinoline

Step 1: [Bis-(4-chloro-phenyl)-methylene]-hydrazine

A solution of bis-(4-chloro-phenyl)-methanone (5.0 g, 19.9 mmol) andhydrazine monohydrate (5 mL, 103 mmol) in ethanol (25 mL) was heated toreflux 18 h, cooled to 21° C., and filtered to afforded the[bis-(4-chloro-phenyl)-methylene]-hydrazine compound as a yellow solid.

Step 2: Diazo bis-(4-chloro-phenyl)-methane

To a solution of [bis-(4-chloro-phenyl)-methylene]-hydrazine from Step 1(2.0 g, 7.5 mmol) in CHCl₃ (20 mL) was added MnO₂ (5.0 g, 57 mmol). Theresulting reaction mixture was stirred 1 h at 21° C., then filtered on abed of MgSO₄ and the filtrate concentrated to provided the diazobis-(4-chloro-phenyl)-methane compound as a purple solid.

Step 3: 6-Isopropyl-8-(3-vinyl-phenyl)-quinoline

To a solution of methyl triphenylphosphonium bromide (5.2 g, 14.6 mmol)in THF (20 mL) at 0° C. was added potassium tert-butoxide (1M, THF, 14.5mL, 14.5 mmol) followed, after 15 min, by Quinoline 04 (3.33 g, 12.1mmol) in THF (5 mL). The resulting reaction mixture was stirred 2 h at0° C., then diluted with a saturated ammonium chloride solution andethyl acetate. The organic extracts were washed (H₂O, brine), dried(MgSO₄), filtered and concentrated. Purification by flash chromatography(eluting with hexane/ethyl acetate, 90:10) provided the6-isopropyl-8-(3-vinyl-phenyl)-quinoline compound.

Step 4:8-{3-[2,2-Bis-(4-chloro-phenyl)-cyclopropyl]-phenyl}-6-isopropyl-quinoline

A solution of the 6-isopropyl-8-(3-vinyl-phenyl)-quinoline from Step 3(230 mg, 0.84 mmol) and the diazo bis-(4-chloro-phenyl)-methane fromStep 2 (530 mg, 2.0 mmol) in benzene (10 mL) was heated to reflux for 18h, cooled to 21° C., and purified by flash chromatography (eluting withhexane/ethyl acetate, 90:10) to provide the8-{3-[2,2-bis-(4-chloro-phenyl)-cyclopropyl]-phenyl}-6-isopropyl-quinolinecompound as a yellow foam.

¹H NMR (400 MHz, acetone-d₆): δ 8.79 (dd, 1H), 8.28 (dd, 1H), 7.73 (d,1H), 7.47-7.39 (m, 4H), 7.33-7.21 (m, 8H), 7.14 (m, 2H), 3.13 (m, 1H),3.03 (dd, 1H), 2.18 (dd, 1H), 1.80 (dd, 1H), 1.36 (d, 6H).

EXAMPLE 1098-{3-[2,2-Bis-(4-methanesulfonyl-phenyl)-cyclopropyl]-phenyl}-6-isopropyl-quinoline

Step 1: Bis-(4-methylsulfanyl-phenyl)-methanol

To a solution of 4-bromothioanisole (1.06 g, 5.2 mmol) in THF (20 mL) at−78° C. was added BuLi (2.3M, hexane, 2.2 mL, 5 mmol) dropwise. After 30min at −78° C., 4-methylthiobenzaldehyde (685 mg, 4.5 mmol) was added.After 20 min., the resulting reaction mixture was diluted with asaturated ammonium chloride solution and ethyl acetate. The organicextracts were washed (H₂O, brine), dried (MgSO₄), filtered andconcentrated. Purification by flash chromatography (eluting withhexane/ethyl acetate, 80:20) provided thebis-(4-methylsulfanyl-phenyl)-methanol compound.

Step 2: Bis-(4-methylsulfanyl-phenyl)-methanone

A solution of bis-(4-methylsulfanyl-phenyl)-methanol from Step 1 (1.0 g,3.6 mmol) and MnO₂ (3 g, 35 mmol) in CH₂Cl₂ (30 mL) was stirred at 21°C. for 18 h. The resulting mixture was filtered through a pad of celiteand concentrated. Purification by flash chromatography (eluting withhexane/ethyl acetate, 85:15) provided thebis-(4-methylsulfanyl-phenyl)-methanone compound.

Step 3: Bis-(4-methanesulfonyl-phenyl)-methanone

A solution of bis-(4-methylsulfanyl-phenyl)-methanone from Step 2 (0.9g, 3.2 mmol), NMO (2.2 g, 19 mmol) and OsO₄ (4%, H₂O, 1 mL, 0.16 mmol)in acetone (20 mL) was stirred 18 h at 21° C. The resulting reactionmixture was diluted with a sodium metabisulfite solution and ethylacetate. The organic extracts were washed (H₂O, brine), dried (MgSO₄),filtered and concentrated. Purification by flash chromatography (elutingwith hexane/ethyl acetate, 70:30) provided thebis-(4-methanesulfonyl-phenyl)-methanone compound.

Step 4:8-{3-[2,2-Bis-(4-methanesulfonyl-phenyl)-cyclopropyl]-phenyl}-6-isopropyl-quinoline

The procedures described above in Example 108 were followed, butsubstituting bis-(4-methanesulfonyl-phenyl)-methanone from Step 3instead of bis-(4-chloro-phenyl)-methanone. Purification by flashchromatography (eluting with ethyl acetate/hexane, 3:7) afforded the8-{3-[2,2-bis-(4-methanesulfonyl-phenyl)-cyclopropyl]-phenyl}-6-isopropyl-quinolinecompound as a white solid.

¹H NMR (400 MHz, acetone-d₆): δ 8.81 (dd, 1H), 8.29 (dd, 1H), 7.88 (d,2H), 7.76-7.70 (m, 5H), 7.58 (d, 2H), 7.48-7.40 (m, 4H), 7.21 (t, 1H),7.05 (d, 1H), 3.23 (dd, 1H), 3.14 (m, 1H), 3.09 (s, 3H), 2.93 (s, 3H),2.4 (dd, 1H), 1.97 (dd, 1H), 1.35 (d, 6H).

EXAMPLES 110 and 1113-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-pyridin-4-yl-oxirane-2-carbonitrileand3-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-(1-oxy-pyridin-4-yl)-oxirane-2-carbonitrile

Step 1:3-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-pyridin-4-yl-acrylonitrile

Following the procedures described above in Example 78, Step 2, butsubstituting 4-methanesulfonylacetonitrile for 4-pyridinylacetonitrile,and purification by flash chromatography (eluting with ethylacetate/hexane, 3:7) afforded the3-[3-(6-isopropyl-quinolin-8-yl)-phenyl]-2-pyridin-4-yl-acrylonitrilecompound.

Step 2:3-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-pyridin-4-yl-oxirane-2-carbonitrile

To a solution of3-[3-(6-isopropyl-quinolin-8-yl)-phenyl]-2-pyridin-4-yl-acrylonitrilefrom Step 1 (75 mg, 0.3 mmol) in CH₂Cl₂/MeOH (1:1, 2 mL) was added MMPP(148 mg, 0.3 mmol). The resulting reaction mixture was stirred 18 h at21° C., then diluted with a sodium bicarbonate solution and ethylacetate. The organic extracts were washed (H₂O, brine), dried (MgSO₄),filtered and concentrated. Purification by flash chromatography (elutingwith EtOH/ethyl acetate, 10:90) provided the title compounds.

3-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-pyridin-4-yl-oxirane-2-carbonitrile:¹H NMR (500 MHz, acetone-d₆): δ 8.83 (dd, 1H), 8.74 (m, 2H), 8.32 (dd,1H), 7.95 (d, 1H), 7.90 (m, 1H), 7.81 (d, 1H), 7.79 (d, 1H), 7.61 (m,2H), 7.56 (dd, 2H), 7.49 (dd, 1H), 4.7 (s, 1H), 3.18 (m, 1H), 1.38 (d,3H), 1.37 (d, 3H).

3-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-(1-oxy-pyridin-4-yl)-oxirane-2-carbonitrile:¹H NMR (500 MHz, acetone-d₆): δ 8.83 (dd, 1H), 8.33 (dd, 1H), 8.27 (m,2H), 7.92 (s, 1H), 7.90 (m, 1H), 7.81 (d, 1H), 7.78 (d, 1H), 7.61-7.56(m, 4H), 7.50 (dd, 1H), 4.8 (s, 1H), 3.18 (m, 1H), 1.39 (d, 3H), 1.37(d, 3H).

EXAMPLES 112 and 1133-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-pyridin-2-yl-oxirane-2-carboxylicacid ethyl ester and3-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-(1-oxy-pyridin-2-yl)-oxirane-2-carboxylicacid ethyl ester

Following the procedures described in Example 110, but substituting4-pyridinylacetonitrile for ethyl 2-pyridinylacetate, and purificationby flash chromatography (eluting with EtOH/ethyl acetate, 10:90)provided the title compounds.

3-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-pyridin-2-yl-oxirane-2-carboxylicacid ethyl ester: ¹H NMR (500 MHz, acetone-d₆): δ 8.80 (dd, 1H), 8.29(dd, 1H), 8.05 (d, 1H), 7.76 (d, 1H), 7.61 (m, 1H), 7.57 (s, 1H), 7.53(dd, 1H), 7.50 (d, 1H), 7.46 (dd, 1H), 7.35-7.27 (m, 5H), 5.11 (s, 1H),4.20 (m, 2H), 3.16 (m, 1H), 1.37 (d, 6H), 1.20 (t, 3H).

3-[3-(6-Isopropyl-quinolin-8-yl)-phenyl]-2-(1-oxy-pyridin-2-yl)-oxirane-2-carboxylicacid ethyl ester: ¹H NMR (500 MHz, acetone-d₆): δ 8.83 (dd, 1H), 8.59(d, 1H), 8.31 (dd, 1H), 7.89 (m, 1H), 7.87 (m, 2H), 7.75 (m, 2H), 7.48(m, 3H), 7.42 (m, 1H), 4.9 (s, 1H), 4.05 (m, 2H), 3.18 (m, 1H), 1.39 (d,3H), 1.37 (d, 3H), 0.89 (t, 3H).

Other variations or modifications, which will be obvious to thoseskilled in the art, are within the scope and teachings of thisinvention. This invention is not to be limited except as set forth inthe following claims.

1. A compound represented by (I):

or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl,pyridinone, pyridyl, or pyridyl N-oxide, optionally substituted with 1-5independent —C₁₋₆alkyl, —OH, —CN, halogen, —CF₃,—(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl), —(C₀₋₆alkyl)-SO_(n)—NH—(C₁₋₆alkyl) or5-membered heteroaryl ring containing 1-4 heteroatoms independentlyselected from O, S or N, wherein the 5-membered-ring is optionallysubstituted with C₁₋₆alkyl, and the alkyl group- is optionallysubstituted with 1-3 independent —OH, —CN, halogen, or —CF₃; R₁ ishydrogen, halogen; or a —C₁₋₆alkyl, -cycloC₃₋₆alkyl, —C₁₋₆alkenyl,—C₀₋₄alkyl-C(O)—C₀₋₄alkyl, —C₁₋₆alkoxy, aryl, heteroaryl, —CN,-heterocycloC₃₋₆alkyl, -amino, —C₁₋₆alkylamino,—(C₁₋₆alkyl)(C₁₋₆alkyl)amino, —C₁₋₆alkyl(oxy)C₁₋₆alkyl, —C(O)NH(aryl),—C(O)NH(heteroaryl), —SO_(n)NH(aryl), —SO_(n)NH(heteroaryl),—SO_(n)NH(C₁₋₆alkyl), —C(O)N(C₀₋₆alkyl)(C₀₋₆alkyl),—NH—SO_(n)—(C₁₋₆alkyl), -carbamoyl, —(C₁₋₆alkyl-O—C(CN)-dialkylamino, or—C₀₋₆alkyl)SO_(n)—C₁₋₆alkyl) group, wherein any of the groups isoptionally substituted with 1-5 substituents; wherein each substituentis independently a halogen, —OH, —CN, —C₁-C₆alkyl,—C(O)(heterocycloC₃₋₆alkyl), —C(O)—O—(C₀₋₆alkyl), —C(O)—O-aryl, alkoxy,cycloalkyloxy, acyl, acyloxy, -cycloC₃₋₆alkyl, heterocycloC₃₋₆alkyl,aryl, heteroaryl, pyridyl N-oxide, carbonyl, carbamoyl, or—SO_(n)—(C₁₋₆alkyl); R₂, R₃, R₆, and R₇ are each independently hydrogen,halogen, hydroxyl, —C₁₋₆alkyl, or —C₁₋₆alkoxy, wherein the alkyl andalkoxy are optionally substituted with 1-3 independently halogen or OH;R₄ is hydrogen, halogen, —CN, phenyl, oxadiazolyl, or —C(O)—O—C₀₋₆alkyl,wherein the phenyl, oxadiazolyl, or —C(O)—O—C₀₋₆alkyl is optionallysubstituted with 1-3 independent halogen, CN, CF3, —SO_(n)—C₁₋₆alkyl, orC₁₋₆alkyl substituents, and the alkyl group is optionally substitutedwith OH R5 is hydrogen, hydroxyl, —CN; or a —C₁₋₆alkyl, —C(O)C₁₋₆alkyl,—C(O)-aryl, —C(O)-pyridyl, —C(O)—O—C₀₋₆alkyl, —C(O)—C₃₋₇cycloalkyl,—C₁₋₆alkyl-C₃₋₇cycloalkyl, —C₁₋₆alkyl(C₃₋₇cycloalkyl)₂, —C₁₋₆alkyl-aryl,—C(O)—N(C₀₋₆alkyl)₂, —SO_(n)aryl, —SO_(n)—C₁₋₆alkyl,—SO_(n)—C₃₋₇cycloalkyl, —SO_(n)—N(C₀₋₆alkyl)₂, —P(O)(C₁₋₆alkyl)₂,—P(O)(C₁₋₆alkoxy)₂, phenyl, pyridyl, —SO_(n)imidazolyl,—SO_(n)thiazolyl, 5-membered heteroaryl ring containing 1-4 heteroatomsindependently selected from O, S or N or oxoisoxaphosphinanyl group, anyof which group optionally substituted with 1-6 independent halogen,hydroxyl, —CN, —CF₃, —C₁₋₆alkyl, —SO_(n)—C₁₋₆alkyl, —C(O)—O—C₀₋₆alkyl,or hydroxyC₁₋₆alkyl substituents; or R₅ and R₆ form ═O; or R₆ and R₃form —CH₂— or —O—; and n is 0, 1, or
 2. 2. The compound according toclaim 1, or a pharmaceutically acceptable salt thereof, wherein Ar isphenyl optionally substituted with 1-5 independent —C₁₋₆alkyl, —OH, —CN,halogen, —CF₃, —(C₀₋₆alkyl)-SO_(n)—(C₁₋₆alkyl),—(C₀₋₆alkyl)-SO_(n)—NH—(C₁₋₆alkyl) or 5-membered heteroaryl ringcontaining 1-4 heteroatoms independently selected from O, S or N,wherein the 5-membered-ring is optionally substituted with C₁₋₆alkyl,and the alkyl group- is optionally substituted with 1-3 independent —OH,—CN, halogen, or —CF₃.
 3. The compound according to claim 2, or apharmaceutically acceptable salt thereof, wherein R₄ is hydrogen,halogen, —CN, or —C(O)—O—C₀₋₆alkyl, wherein the —C(O)—O—C₀₋₆alkyl isoptionally substituted with 1-3 independent halogen or C₁₋₄alkylsubstituents.
 4. The compound according to claim 2, or apharmaceutically acceptable salt thereof, wherein R₄ is oxadiazolyloptionally substituted with 1-3 independent halogen or C₁₋₄alkylsubstituents.
 5. The compound according to claim 2, or apharmaceutically acceptable salt thereof, wherein R₆ and R₃ form —CH₂—.6. The compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein Ar is pyridyl or pyridyl N-oxide.
 7. The compoundaccording to claim 6, or a pharmaceutically acceptable salt thereof,wherein R₄ is phenyl optionally substituted with 1-3 independent halogenor C₁₋₄alkyl substituents.
 8. The compound according to claim 6, or apharmaceutically acceptable salt thereof, wherein R₄ is hydrogen,halogen, —CN, or —C(O)—O—C₀₋₆alkyl, wherein the —C(O)—O—C₀₋₆alkyl isoptionally substituted with 1-3 independent halogen or C₁₋₄alkylsubstituents.
 9. The compound according to claim 6, or apharmaceutically acceptable salt thereof, wherein R₆ and R₃ form —O—.10. The compound according to claim 1, represented by

or a pharmaceutically acceptable salt thereof.
 11. The compoundaccording to claim 1 represented by

or a pharmaceutically acceptable salt thereof.
 12. The compoundaccording to claim 1 represented by

or a pharmaceutically acceptable salt thereof.
 13. The compoundaccording to claim 1 represented by

or a pharmaceutically acceptable salt thereof.
 14. The compoundaccording to claim 1 represented by

or a pharmaceutically acceptable salt thereof.
 15. The compoundaccording to claim 1 represented by

or a pharmaceutically acceptable salt thereof.
 16. A pharmaceuticalcomposition comprising a therapeutically effective amount of thecompound according to claim 1 or a pharmaceutically acceptable saltthereof; and a pharmaceutically acceptable carrier.
 17. A method ofinhibiting PDE-4 in a mammal comprising administering to the mammal atherapeutically effective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof.
 18. The method of claim 17wherein the mammal has a condition selected from asthma, chronicbronchitis, or chronic obstructive pulmonary disease.
 19. The method ofclaim 17 wherein the mammal has a condition selected from laminitis inhorses, or colic in horses.
 20. The method of claim 17 wherein themammal has a condition selected from endotoxic shock, septic shock,ulcerative colitis, bacterial or fungal induced sepsis, viral inducedsepsis, bacterial or fungal induced septic shock, or viral inducedseptic shock.
 21. The method of claim 17 wherein the mammal has acondition selected from Crohn's disease, reperfusion injury of themyocardium and brain, inflammatory arthritis, chronicglomerulonephritis, urticaria, rheumatoid arthritis, transplantrejection, graft versus host disease, inflammation-mediated chronictissue degeneration, cytokine-mediated chronic tissue degeneration,osteoarthritis, or muscle wasting.
 22. The method of claim 17 whereinthe mammal has a condition selected from adult respiratory distresssyndrome, chronic obstructive pulmonary disease in animals, diabetesinsipidus, allergic rhinitis, allergic conjunctivitis, vernalconjunctivitis, arterial restenosis, ortherosclerosis, atherosclerosis,neurogenic inflammation, pain, cough, ankylosing spondylitis,hypersecretion of gastric acid, cancer, cachexia, depression, memoryimpairment, tumour growth, or cancerous invasion of normal tissues. 23.The method of claim 17 wherein the mammal has a condition selected frommonopolar depression, acute and chronic neurodegenerative disorders withinflammatory components, Parkinson disease, Alzheimer's disease, spinalcord trauma, head injury, or multiple sclerosis.